Compounds

ABSTRACT

The present invention relates to compounds of formula I which are antagonists of gonadotropin releasing hormone (GnRH) activity. The invention also relates to pharmaceutical formulations, the use of a compound of the present invention in the manufacture of a medicament, a method of therapeutic treatment using such a compound and processes for producing the compounds.

[0001] The present invention relates to compounds which are antagonistsof gonadotropin releasing hormone (GnRH) activity. The invention alsorelates to pharmaceutical formulations, the use of a compound of thepresent invention in the manufacture of a medicament, a method oftherapeutic treatment using such a compound and processes for producingthe compounds.

BACKGROUND TO THE INVENTION

[0002] Gonadotropin releasing hormone (GnRH) is a decapeptide that issecreted by the hypothalamus into the hypophyseal portal circulation inresponse to neural and/or chemical stimuli, causing the biosynthesis andrelease of luteinizing hormone (LH) and follicle-stimulating hormone(FSH) by the pituitary. GnRH is also known by other names, includinggonadoliberin, LH releasing hormone (LHRH), FSH releasing hormone (FSHRH) and LH/FSH releasing factor (LH/FSH RF).

[0003] GnRH plays an important role in regulating the action of LH andFSH (by regulation of their levels), and thus has a role in regulatingthe levels of gonadal steroids in both sexes, including the sex hormonesprogesterone, oestrogens and androgens. More discussion of GnRH can befound in WO 98/5519 and WO 97/14697, the disclosures of which areincorporated herein by reference.

[0004] It is believed that several diseases would benefit from theregulation of GnRH activity, in particular by antagonising suchactivity. These include sex hormone related conditions such as sexhormone dependent cancer, benign prostatic hypertrophy and myoma of theuterus. Examples of sex hormone dependent cancers are prostatic cancer,uterine cancer, breast cancer and pituitary gonadotrophe adenoma.

[0005] The following disclose compounds purported to act as GnRHantagonists: WO 00/04013, WO 99/41252, WO 99/41251, WO 98/55123, WO97/21704, WO 97/21703, WO 97/21707, WO 97/21435, WO 97/44041, WO98/55119, WO 99/51596 and WO 97/14697.

[0006] It would be desirable to provide further compounds, suchcompounds being GnRH antagonists.

SUMMARY OF THE INVENTION

[0007] The present invention accordingly provides a compound of formulaI or a pharmaceutically acceptable salt or solvate thereof

[0008] For A, either:

[0009] (i) A represents a single bond; optionally substituted C1 to C8alkylene; a C2 to C12 group having at least one alkene double bond; a 3-to 8-membered heterocyclic ring containing from 1 to 4 heteroatomsindependently selected from O, N and S or —R—Ar—R′—, where R and R′ areindependently selected from a bond, optionally substituted C1 to C8alkylene and a C2 to C12 group having at least one alkene double bond;and Ar represents optionally substituted aryl; or

[0010] (ii) the structure N—A(—R4) represents a 3- to 8-memberedheterocyclic ring optionally containing from 1 to 3 further heteroatomsindependently selected from O, N and S, N—A(—R4) being optionallysubstituted;

[0011] B represents a bond or optionally substituted C1 to C5 alkylene;

[0012] C represents a mono- or bi-cyclic aromatic ring structureoptionally having at least one substituent selected from CN; NR5R6; anoptionally substituted C1 to C8 alkyl; optionally substituted C1 to C8alkoxy; halogen;

[0013] D represents hydrogen; optionally substituted C1 to C8 alkyl; or(CH₂)_(b)—R, wherein R represents C3 to C8 cycloalkyl;

[0014] E is selected from an optionally substituted 3- to 8-memberedheterocyclic ring containing is from 1 to 4 heteroatoms independentlyselected from O, N and S; II; III; IV; V; VI, VII, VIIa, VIIb, VIIc, andVIId,

[0015]  wherein het represents an optionally substituted 3- to8-membered heterocyclic ring containing from 1 to 4 heteroatomsindependently selected from O, N and S;

[0016] F is optionally substituted and represents phenyl or a 3- to8-membered heterocyclic ring containing from 1 to 4 heteroatomsindependently selected from O, N and S;

[0017] For X and V, either:

[0018] (iii) X represents N and Y represents CN or H; or X represents CHand Y represents NO₂; or

[0019] (iv) X—Y represents O;

[0020] For R1 and R2, either:

[0021] (v) R1 and R2 ae independently selected from hydrogen andoptionally substituted C1 to C8 alkyl; or

[0022] (vi) R1 and R2 together represent carbonyl; or

[0023]  represents an optionally substituted 3- to 8-memberedheterocyclic ring containing from 1 to 3 further heteroatomsindependently selected from O, N and S, and R2 meets the definition inoption (v);

[0024] is R3 meets the definition in option (vii) or represents hydrogenor optionally substituted C1 to C8 alkyl;

[0025] R4 meets the definition in option (ii) or represents hydrogen oroptionally substituted C1 to C8 alkyl;

[0026] R5 and R6 are independently selected from H; optionallysubstituted C1 to C8 alkyl and optionally substituted aryl;

[0027] For R7 and R7a, either:

[0028] (viii) R7 and R7a are independently selected from H or optionallysubstituted C1 to C8 alkyl; or

[0029]  represents an optionally substituted 3 to 7-membered cycloalkylring;

[0030] For R8 and R9, either:

[0031] (x) R8 is selected from H; optionally substituted C1 to C8 alkyl;optionally substituted aryl; —R—Ar, where R represents C1 to C8 alkyleneand Ar represents optionally substituted aryl; and optionallysubstituted 3- to 8-membered heterocyclic ring optionally containingfrom 1 to 3 further heteroatoms independently selected from O, N and S;and R9 is selected from H; optionally substituted C1 to C8 alkyl andoptionally substituted aryl; or

[0032] (xi) wherein E represents structure II or III, NR8(-R9)represents an optionally substituted 3- to 8-membered heterocyclic ringoptionally containing from 1 to 3 further heteroatoms independentlyselected from O, N and S; or

[0033] (xii) wherein E represents structure VI,

[0034]  represents an optionally substituted 3- to 8-memberedheterocyclic ring optionally containing from 1 to 4 heteroatomsindependently selected from O, N and S;

[0035] b represents zero or an integer from 1 to 6.

[0036] In one embodiment, a compound of formula I or a pharmaceuticallyacceptable salt or solvate thereof is provided, with the proviso that acompound wherein X represents CH, Y represents NO₂, N—A(—R4) meets thedefinition in option (ii) and F represents optionally substituted phenylis excluded.

[0037] The present invention also provides a pharmaceutical formulationcomprising such a compound and a pharmaceutically acceptable diluent orcarrier.

[0038] Furthermore, the present invention provides the following uses ofthe compound:

[0039] (a) Use in the manufacture of a medicament, for antagonisinggonadotropin releasing hormone activity.

[0040] (b) Use in the manufacture of a medicament for administration toa patient, for reducing the secretion of luteinising hormone by thepituitary gland of the patient.

[0041] (c) Use in the manufacture of a medicament for administration toa patient, for therapeutically treating and/or preventing a sex hormonerelated condition in the patient.

[0042] The present invention also relates to a method of antagonisinggonadotropin releasing hormone activity in a patient, comprisingadministering the compound to the patient.

[0043] In addition, the invention provides a process of producing thecompound.

DETAILED DESCRIPTION OF THE INVENTION

[0044] As discussed above, the present invention provides a compound offormula I or a pharmaceutically acceptable salt or solvate thereof

[0045] For A, either:

[0046] (i) A represents a single bond; optionally substituted C1 to C8alkylene (preferably, C1 to C4 alkylene, for example methylene orethylene); a C2 to C12 (preferably, C2 to C8) group having at least one(eg, 1, 2 or 3) alkene double bond; a 3- to 8-membered heterocyclic ringcontaining from 1 to 4 heteroatoms independently selected from O, N andS (preferably a saturated monocyclic 5-6 membered heterocyclic ring) or—R—Ar—R′—, where R and R′ are independently selected from a bond,optionally substituted C1 to C8 alkylene (preferably, C1 to C4 alkylene,for example methylene or ethylene) and a C2 to C12 (preferably, C2 toC8) group having at least one (eg, 1, 2 or 3) alkene double bond; and Arrepresents optionally substituted aryl (eg, optionally substitutedphenyl); or

[0047] (ii) the structure N—A(—R4) represents a 3- to 8-memberedheterocyclic ring (preferably, a 5- or 6-membered monocyclic ring)optionally containing from 1 to 3 (eg, 1) further heteroatomsindependently selected from O, N and S, N—A(—R4) being optionallysubstituted.

[0048] B represents a bond or optionally substituted C1 to C5 alkylene(preferably, C1 to C4 alkylene, for example methylene or ethylene).

[0049] C represents a mono- or bi-cyclic aromatic ring structure(preferably, phenyl, pyridyl or thienyl) optionally having at least onesubstituent (eg, 1, 2 or 3 substituents) selected from CN; NR5R6; anoptionally substituted C1 to C8 alkyl (preferably, C1 to C4 alkyl, eg,methyl); optionally substituted C1 to C8 alkoxy (preferably, C1 to C6alkoxy, eg, methoxy); halogen (eg, F, Br or Cl).

[0050] Preferably, C represents

[0051] wherein Me represents methyl.

[0052] D represents hydrogen; optionally substituted C1 to C8 alkyl(preferably, C1 to C6 alkyl, eg, methyl); or (CH₂)_(b)—R, wherein Rrepresents C3 to C8 cycloalkyl (eg, C3, C4, C5 or C6 cycloalkyl).

[0053] E is selected from an optionally substituted 3- to 8-memberedheterocyclic ring (preferably, a 5- or 6-membered monocyclic ring)containing from 1 to 4 (eg, 1 or 2) heteroatoms independently selectedfrom O, N and S; II; III; IV; V; VI, VII, VIIa, VIIb, VIIc, and VIId

[0054]  wherein het represents an optionally substituted 3- to8-membered heterocyclic ring (preferably, a 5- or 6-membered monocyclicring) containing from 1 to 4 (eg, 1 or 2) heteroatoms independentlyselected from O, N and S.

[0055] Preferably E is selected from a group of formula II, VIIa, VIIb,VIIc or VIId:

[0056] Further preferably E is selected from one of the followinggroups:

[0057] Yet further preferably E is selected from one of the followinggroups:

[0058] wherein Me represents methyl.

[0059] Most preferably E is selected from one of the following groups:

[0060] Preferably the group —(CH₂)₀₋₂—F represents —(CH₂)₀₋₁—F. Mostpreferably F is linked to A via a direct bond.

[0061] F is optionally substituted and represents phenyl or a 3- to8-membered heterocyclic ring (preferably, a 5- or 6-membered monocyclicring) containing from 1 to 4 (eg, 1 or 2) heteroatoms independentlyselected from O, N and S.

[0062] Preferably, F is optionally substituted and represents pyridyl,VIII, IX, X, XI, XII, XIII, XIV or XIVa

[0063] wherein

[0064] R10 represents hydrogen; optionally substituted C1 to C8 alkyl(preferably, C1 to C6 alkyl, eg, methyl); OH; halogen (eg, F, Cl or Br);CN; C1 to C8 alkoxy (preferably, C1 to C6 alkoxy, eg, methoxy), or CF₃;and

[0065] R10′ represents hydrogen or optionally substituted C1 to C8 alkyl(preferably, C1 to C6 alkyl, eg, methyl).

[0066] For X and Y, either:

[0067] (iii) X represents N and Y represents CN or H; or X represents CHand Y represents NO₂; or

[0068] (iv) X—Y represents O.

[0069] For R1 and R2, either:

[0070] (v) R1 and R2 are independently selected from hydrogen andoptionally substituted C1 to C8 alkyl (preferably, C1 to C6 alkyl, eg,methyl); or

[0071] (vi) R1 and R2 together represent carbonyl; or

[0072] (vii)

[0073]  represents an optionally substituted 3- to 8-memberedheterocyclic ring (preferably, a 5- or 6-membered monocyclic ring)containing from 1 to 3 (eg, 1 or 2) further heteroatoms independentlyselected from O, N and S, and R2 meets the definition in option (v).

[0074] In one embodiment, R1 and R2 each represent H and B represents C1alkylene.

[0075] R3 meets the definition in option (vii) or represents hydrogen oroptionally substituted C1 to C8 alkyl (preferably, C1 to C6 alkyl, eg,methyl).

[0076] R4 meets the definition in option (ii) or represents hydrogen oroptionally substituted C1 to C8 alkyl (preferably, C1 to C6 alkyl, eg,methyl).

[0077] R5 and R6 are independently selected from H; optionallysubstituted C1 to C8 alkyl is (preferably, C1 to C6 alkyl, eg, methyl);and optionally substituted aryl (eg, phenyl).

[0078] For R7 and R7a, either:

[0079] (viii) R7 and R7a are independently selected from H or optionallysubstituted C1 to C8 alkyl (preferably, C1 to C6 alkyl, eg, methyl; inone embodiment R7 and R7a are both methyl); or

[0080] (ix)

[0081]  represents an optionally substituted 3 to 7-membered (eg, 3-,4-, 5- or 6-membered) cycloalkyl ring;

[0082] For R8 and R9, either:

[0083] (x) R8 is selected from H; optionally substituted C1 to C8 alkyl(preferably, C1 to C6 alkyl, eg, methyl; in one embodiment both R8 andR9 are ethyl); optionally substituted aryl (eg, optionally substitutedphenyl); —R—Ar, where R represents C1 to C8 alkylene (preferably, C1 toC6 alkylene, eg, methylene or ethylene) and Ar represents optionallysubstituted aryl (eg, optionally substituted phenyl); and an optionallysubstituted 3- to 8-membered heterocyclic ring (preferably, a 5- or6-membered monocyclic ring) containing from 1 to 3 (eg, 1 or 2) furtherheteroatoms independently selected from O, N and S; and

[0084] R9 is selected from H; optionally substituted C1 to C8 alkyl(preferably, C1 to C6 alkyl, eg, methyl) and optionally substituted aryl(eg, optionally substituted phenyl); or

[0085] (xi) wherein E represents structure II or III, NR8(-R9)represents an optionally substituted 3- to 8-membered heterocyclic ring(preferably, a 5- or 6-membered monocyclic ring) containing from 1 to 3(eg, 1 or 2) further heteroatoms independently selected from O, N and S;or

[0086] (xii) wherein E represents structure VI,

[0087]  represents an optionally substituted 3- to 8-memberedheterocyclic ring (preferably, a 5- or 6-membered monocyclic ring)containing from 1 to 4 (eg, 1 or 2) heteroatoms independently selectedfrom O, N and S.

[0088] b represents zero or an integer from 1 to 6.

[0089] In the present specification, unless otherwise indicated, analkyl, alkylene or alkenyl moiety may be linear or branched.

[0090] The term “alkylene” refers to the group —CH₂—. Thus, C₈ alkylenefor example is —(CH₂)₈—

[0091] The term “aryl” refers to phenyl or naphthyl.

[0092] The term “halo” refers to fluoro, chloro, bromo or iodo.

[0093] The term “heterocyclic ring” refers to a 5-10 membered aromaticmono or bicyclic ring or a 5-10 membered saturated or partiallysaturated mono or bicyclic ring, said aromatic, saturated or partiallyunsaturated rings containing up to 5 heteroatoms independently selectedfrom nitrogen, oxygen or sulphur, linked via ring carbon atoms or ringnitrogen atoms where a bond from a nitrogen is allowed, for example nobond is possible to the nitrogen of a pyridine ring, but a bond ispossible through the 1-nitrogen of a pyrazole ring. Examples of 5- or6-membered aromatic heterocyclic rings include pyrrolyl, furanyl,imidazolyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl,isoxazolyl, oxazolyl, 1,2,4 oxadiazolyl, isothiazolyl, thiazolyl andthienyl. A 9 or 10 membered bicyclic aromatic heterocyclic ring is anaromatic bicyclic ring system comprising a 6-membered ring fused toeither a 5 membered ring or another 6 membered ring. Examples of 5/6 and6/6 bicyclic ring systems include benzofuranyl, benzimidazolyl,benzthiophenyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl,benzisoxazolyl, indolyl, pyridoimidazolyl, pyrimidoimidazolyl,quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, phthalazinyl,cinnolinyl and naphthyridinyl. Examples of saturated or partiallysaturated heterocyclic rings include pyrrolinyl, pyrrolidinyl,morpholinyl, piperidinyl, piperazinyl, dihydropyridinyl anddihydropyrimidinyl.

[0094] The term “aromatic ring” refers to a 5-10 membered aromatic monoor bicyclic ring optionally containing up to 5 heteroatoms independentlyselected from nitrogen, oxygen or sulphur. Examples of such “aromaticrings” include: phenyl, pyrrolyl, furanyl, imidazolyl, triazolyl,pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl, isoxazolyl, oxazolyl,1,2,4 oxadiazolyl, isothiazolyl, thiazolyl and thienyl. Preferredaromatic rings include ′phenyl, thienyl and pyridyl.

[0095] Where optional substitution is mentioned at various places, thisrefers to one, two, three or more optional substituents. Unlessotherwise indicated above (ie, where a list of optional substituents isprovided), each substituent can be independently selected from C1 to C8alkyl (eg, C2 to C6 alkyl, and most preferably methyl); O(C3 to C8cycloalkyl), preferably O-cyclopropyl, or O-cyclobutyl or O-cyclopentyl;O(C1 to C6 alkyl), preferably Omethyl or O(C2 to C4 alkyl); halo,preferably Cl or F; CHal₃, CHHal₂, CH₂Hal, OCHal₃, OCHHal₂ or OCH₂Hal,wherein Hal represents halogen (preferably F); CH₂OR, NRCOR′, NRSO₂R′ orN—R—R′, wherein R and R′ independently represent H or C1 to C8 alkyl(preferably methyl or C2 to C6 alkyl or C2 to C4 alkyl) , or N—R—R′represents an optionally substituted C3 to C8, preferably C3 to C6,heterocyclic ring optionally containing from 1 to 3 further heteroatomsindependently selected from O, N and S; H; or COOR″ or COR″, R″representing H, optionally substituted phenyl or C1 to C6 alkyl(preferably methyl, ethyl, i-propyl or t-butyl). For optionalsubstitution of the heterocyclic ring represented by N—R—R′, at leastone (eg, one, two or three) substituents may be provided independentlyselected from C1 to C6 alkyl (eg, C2 to C4 alkyl, more preferablymethyl); phenyl; OCF₃; OCHF₂; —O(C1-C8 alkyl), preferably —O-methyl,—O-ethyl or —O(C3 to C6 alkyl); —C(O)O(C1-C8 alkyl), preferably—C(O)O-methyl, —C(O)O-ethyl, —C(O)O-tert-butyl or —C(O)O(C3 to C6alkyl); —C(O)O-phenyl; —O-phenyl; —C(O) (C1-C8 alkyl), preferably—C(O)-methyl, —C(O)-ethyl or —C(O)(C3 to C6 alkyl); —C(O)OH; —S(C1-C8alkyl), preferably —S-methyl, —S-ethyl or —S(C3 to C6 alkyl); OH;halogen (eg, F, Cl or Br); NR*R** where R* and R** are independently Hor C1 to C6 alkyl (preferably C2 to C4 alkyl, more preferably methyl,most preferably R=R′=methyl); and nitro.

[0096] Where optional substitution of a ring is mentioned at variousplaces, this most preferably refers to one, two, three or moresubstituents selected from C1 to C8 alkyl (eg, C2 to C6 alkyl, and mostpreferably methyl); —O(C1 to C8 alkyl), preferably —O-methyl, —O-ethylor —O(C3 to C6 alkyl); halogen (eg, F, Cl or Br); CN; and NO₂.

[0097] A further preferred group of compounds of the invention comprisesa compound of Formula Ia:

[0098] wherein:

[0099] A, B, C, D, E, F, X, Y, R³ and R⁴ are as defined above; or asalt, pro-drug or solvate thereof.

[0100] Particularly preferred compounds according to the presentinvention are:

[0101]2-(2-(3,5-dimethylphenyl)-3-{2-[(2-nitro-1-{[2-(4-pyridinyl)ethyl]amino}ethenyl)amino]ethyl}-1H-indol-5-yl)-N,N-diethyl-2-methylpropanamide;

[0102]2-[3-2{-[((cyanoimino){[2-(4-pyridinyl)ethyl]amino}methyl)amino]ethyl}-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-N,N-diethyl-2-methylpropanamide;

[0103]2-[3-2{-[((cyanoimino){[2-(2-pyridinyl)ethyl]amino}methyl)amino]ethyl}-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-N,N-diethyl-2-methylpropanamide;

[0104]2-[3-2{-[((cyanoimino){[2-(1-imidazoyl)ethyl]amino}methyl)amino]ethyl}-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-N,N-diethyl-2-methylpropanamide;

[0105]2-[2-(3,5-dimethylphenyl)-3-(2-{[(phenethylamino)carbonyl]amino}ethyl)-1H-indol-5-yl]-N,N-diethyl-2-methylpropanamide;

[0106]2-[2-(3,5-dimethylphenyl)-3-(2-{[(4-pyridinyl)ethyl]amino)carbonyl]amino}ethyl)-1H-indol-5-yl]-N,N-diethyl-2-methylpropanamide;

[0107]2-[3-2{-[((cyanoimino){[3-(4-methylpiperazino)propyl]amino}methyl)amino]ethyl}-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-N,N-diethyl-2-methylpropanamide;

[0108]2-[3-2-{-[((cyanoimino){[2-(2-piperidinyl)ethyl]amino}methyl)amino]ethyl}-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-N,N-diethyl-2-methylpropanamide;

[0109]2-[3-[2-({(cyanoimino)[3-(4-pyridinyl)-pyrrolidin-1-yl]methy}lamino)ethyl]-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-N,N-diethyl-2-methylpropanamide;

[0110]2-[3-2{-[((cyanoimino){[2-(4-pyridinyl)ethyl]aminomethyl}methyl)amino]ethyl}-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-N,N-diethyl-2-methylpropanamide;

[0111]2-[3-[2-[(2-nitro-1-([3-(4-pyridinyl)-pyrrolidin-1-yl]ethenyl}amino)ethyl]-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-N,N-diethyl-2-methylpropanamide;

[0112]2-[3-[2-((carbonyl)[3-(4-pyridinyl)-pyrrolidin-1-yl]amino)ethyl]-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-N,N-diethyl-2-methylpropanamide;

[0113]2-[3-[2-({(imino)[3-(4-pyridinyl)-pyrrolidin-1-yl]methyl}amino)ethyl]-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-N,N-diethyl-2-methylpropanamide;and

[0114]2-[3-[2-({(cyanoimino)[3-(4-pyridinyl)-pyrrolidin-1-yl]methyl}amino)ethyl]-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-1-cyclopropylcarboxylicacid-diethylamide.

[0115] The compounds of formula I can be prepared by a processcomprising a step selected from (a) to (e) as follows:

[0116] (a) Reaction of XV as follows

[0117] (b) Cleavage of the CN group of XVI in the presence of acid toproduce XVII

[0118] (c) Reaction of XVIII as follows

[0119] (d) Reaction of XX as follows

[0120] (e) Reaction of XXII as follows

[0121] It will be appreciated by those skilled in the art that in theprocesses of the present invention certain functional groups such ashydroxyl or amino groups in the starting reagents or intermediatecompounds may need to be protected by protecting groups. Thus, thepreparation of the compounds of formula I may involve, at an appropriatestage, the addition and subsequent removal of one or more protectinggroups.

[0122] The protection and deprotection of functional groups is describedin ‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOmie,Plenum Press (1973) and ‘Protective Groups in Organic Synthesis’, 2ndedition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1991).

[0123] The invention also contemplates pharmaceutically acceptable saltsand solvates of compounds of formula I.

[0124] Experimental

[0125] General Reaction Schemes

[0126] In the following schemes, group C has been depicted assubstituted phenyl for illustration purposes only. Other definitions ofC are also appropriate.

[0127] Tryptamines, such as 3 can be synthesised by the classic Fisherindole synthesis reaction by the condensation of a hydrazine 1 and aketone 2, bearing hydrogen atoms α to the carbonyl (Scheme a). Treatmentof these reactants in a suitable solvent, such as acetic acid, ethanol,tert-butanol, toluene, in the presence of an acid, such as sulphuric,hydrochloric, polyphosphoric and/or a Lewis acid, for example, borontrifluoride, zinc chloride, magnesium bromide, at elevated temperatures(for example 100° C.), gives the desired product. R represents aprotecting group, eg tert-butylcarbamate or phthalimide.

[0128] Tryptamines, such as represented in structure 5, can also be madeusing aldehydes 4, bearing hydrogen atoms α to the carbonyl, bycyclisation using the conditions above. In this case the substituent atthe 2-position must be added later (see scheme d).

[0129] Tryptamine may also be synthesised utilising the Granburgreaction, wherein a hyradazine 1 is mixed with ketone 6, bearing achlorine atom γ to the carbonyl, and heated in a suitable solvent suchas ethanol, tert-butanol, toluene at a temperature between 50° C. and120° C. (Scheme c).

[0130] The tryptamine 5 can be treated with a ‘bromine source’, such asmolecular bromide, pyridinium tibromide, pyrrolidone hydrobromide orpolymer supported reagent equivalents, in an inert solvent such aschloroform, methylene chloride at −10° C. to 25° C. to yield the 2-bromocompound 8 (Scheme d). Reaction under Suzuki conditions with apalladium(0) catalyst, a weak base such aqueous sodium carbonate orsaturated sodium hydrogen carbonate and the like, and a substituted arylboronic acid from commercial sources or prepared (as described in:Gronowitz, S.; Hornfeldt, A.-B.; Yang, Y.,-H Chem. Sci. 1986, 26,311-314), in an inert solvent such as toluene, benzene, dioxane, THF,DMF and the like, with heating between 25° C. and 100° C., preferably80° C., for a period of 1-12 hours, to give the desired compound 3.

[0131] The hydrazines 1 can be purchased from commercial sources eitheras a free base or suitable salt (e.g. hydrochloride), which are bothacceptable under the reaction conditions. Hydrazines may be synthesisedby the two-step process of diazotisation of an aniline, under thepreferred conditions of concentrated hydrochloric acid sodium nitrite ata temperature between −10° C. and −5° C., then reduction under thepreferred conditions of tin(II) chloride in concentrated hydrochloricacid at a temperature between −10° C. and −5° C.

[0132] Substituted ketones 2 can be prepared, as outlined in Scheme estarting from appropriate acid chlorides such as 9. Treatment of theacid chloride with N,N-dimethylhydroxylamine hydrochloride in thepresence of an amine base such as triethylamine, and a suitable solventsuch as methylene chloride at a temperature of −10° C. to 25° C., yieldsthe amide 10. Further reaction with a substituted aryl organolithium(prepared essentially as described in Wakefield B. J.; OrganolithiumMethods Academic Press Limited, 1988, pp. 27-29 and references therein)in an inert solvent such as tetrahydrofuran, diethyl ether, benzene,toluene or mixture thereof and the like, at a temperature between −100°C. and 0° C. then quenching of the reaction mixture with a mineral acidsuch as hydrochloric acid, yields the aryl ketone 2.

[0133] Commencing with a readily available amino acid with a suitablechain length [a] 11, the nitrogen atom can be brought in at thebeginning of the synthesis by the route shown in Scheme f. Protection ofthe amine group of 11 with a tert-butylcarbamate group is achieved bycondensation with di-tert-butyl dicarbonate in the presence of an aminebase, for example triethylamine, in an inert solvent such as methylenechloride, chloroform, benzene, toluene, tetrahydrofuran and mixturesthereof and the like, at a temperature of −10° C. to 25° C. Coupling ofthe acid product with N,N-dimethylhydroxylamine in the presence of acoupling reagent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDC) or 1,3-dicyclohexylcarbodiimide (DCC) or the like,with or without 1-hydroxybenotriazole (HOBt), and suitable amine base,such as triethylamine and the like, in an inert solvent such asmethylene chloride, chloroform, dimethylformamide, or mixture thereof,at or near room temperature for a period of 3 to 24 h provided thecorresponding coupled product 12. Following the same route describedabove for scheme d, the aryl group can then be installed.

[0134] Scheme g illustrates another method for the synthesis of ketonesuch as 2 and 16, where the nitrogen group is introduced at a latterstage. As above a Weinreb amide 14 can be synthesised from an acidchloride. Treatment with the required amine, in an inert solvent such asTHF, toluene, water and the such like can displace the group X to give17. As above the aryl group can be introduced by displacement of theWeinreb amide with a suitable aryl lithium nucleophile. Alternativelythe nitrogen atom can be introduced already protected as a phthalimideby displacement of the group x by potassium phthalimide, or similar saltthereof, by heating in an inert polar solvent such as DMF, DMSO, THF,toluene with or without the presence of a catalyst such astetrabutylammonium iodide and the such like, to yield the compound 15.Again displacement of the Weinreb amide with an organolithium speciescompletes the synthesis of a ketone suitable for cyclisation under theFischer condition described above for indole synthesis.

[0135] An alternative approach to a phthalimide protected nitrogenketone, such as 16, can be taken by firstly treating a lactone, with anorganolithium species as in the above schemes in a suitable solvent suchas THF or ether at a low temperature of between −100° C. and −50° C. toyield a primary alcohol 18 (Scheme h). The hydroxyl function of 18 isreplaced with a phthalimide group by a Mitsunobu reaction with anactivating agent such as diethyldiazocarboxylate (DEAD),diisopropyldiazocarboxlate or the like with triphenylphosphine,tri-butylphosphine and the like, in an inert solvent such as benzene,toluene, tetrahydrofuran or mixtures thereof to give the desired ketone16.

[0136] If the group D was not present on the starting hydrazine beforecyclisation to form an indole it may be added post cyclisation by analkylation reaction (19→3). The indole is deprotonated by a strong base,such as sodium hydride, n-butyl lithium, lithium diisopropylamine,sodium hydroxide, potassium tert-butoxide in a suitable inert solventsuch as THF, DMF, DMSO and the such like, and an alkyl halide added andthe mixture stirred at room temperature.

[0137] Depending on the route used above a tryptamine 20 suitable forconversion to a cyano-guandine can be formed by removal of theprotecting group, for example if a tert-butylcarbamate group was usedthen removal is accomplished using a strong acid, for exampletrifluoroacetic acid or hydrochloric acid in an inert solvent such asmethylene chloride, chloroform, THF or dioxane at a temperature between−20° C. and 25° C. A phthalimide group, for example, can be removed byhydrazine in a suitable solvent for example methanol, ethanol, methylenechloride, chloroform, THF dioxane at a temperature between −20° C. and25° C. The primary amine 20 can be converted to a cyano-guanidine 22 bythe two step process of reaction with diphenyl cyanocarbonimidate in aninert organic solvent such as isoproplyl alcohol, methylene chloride,chloroform, benzene, tetrahydrofuran and the like, at a temperaturebetween −20° C. and 50° C., followed by condensation with anappropriately substituted amine in an inert organic from the list above,with heating at a temperature between −20° C. and 100° C. (Scheme I20→21→22). Further treatment of 22 with 2 molar Hydrochloric acid inmethanol at elevated temperature yields guanidine compounds 23.

[0138] Similarly, reaction with 1,1′-bis(methylthio)-2-nitroethylene inan inert solvent such methylene chloride, chloroform, benzene,tetrahydrofuran and the like, followed by condensation with anappropriately substituted amine in an inert organic solvent from thelist above yields the nitroethyleneimidazo[1,2-a]pyridine 25 (Scheme j,20→24→25).

[0139] Again in a similar fashion the suitable tryptamine 20, derivedfrom deprotection, can be converted to a urea by either direct treatmentwith an iso-cyanate in an inert solvent such as methylene chloride,chloroform or THF and the such like, or by a two step procedure ofreaction with triphosgene (20→27) followed by addition of an amine(27→26), bearing the required substitution to yield 26.

EXAMPLES

[0140] The invention will now be illustrated with the followingnon-limiting Examples in which, unless otherwise stated:

[0141] (i) evaporations were carried out by rotary evaporation in vacuoand work-up procedures were carried out after removal of residual solidssuch as drying agents by filtration;

[0142] (ii) operations were carried out at room temperature, that is inthe range 18-25° C. and under an atmosphere of an inert gas such asargon or nitrogen;

[0143] (iii) yields are given for illustration only and are notnecessarily the maximum attainable;

[0144] (iv) the structures of die end-products of the Formula I wereconfirmed by nuclear (generally proton) magnetic resonance (NMR) andmass spectral techniques; proton magnetic resonance chemical shiftvalues were measured on the delta scale and peak multiplicities areshown as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br,broad; q, quartet, quin, quintet;

[0145] (v) intermediates were not generally fully characterised andpurity was assessed by thin layer chromatography (TLC), high-performanceliquid chromatography (HPLC), infra-red (IR) or NMR analysis;

[0146] (vi) chromatography was performed on silica (Merck Keiselgel:Art.9385); Abbreviations brine a saturated solution of sodium chloridein distilled water DCC 1,3-dicyclohexylcarbodiimide DEADdiethyldiazocarboxylate DMSO Dimethyl sulphoxide DMF dimethylformamideEDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride HOBt1-hydroxybenotriazole IPA isopropyl alcohol RM reaction mixture RT roomtemperature THF tetrahydrofuran

Example 1

[0147]

[0148] 4-Pyrrolidin-3-yl pyridine (1.00 g, 6.76 mmol) was added to astirred suspension of L (1.00 g, 1.80 mmol) in IPA (5 ml) and themixture heated at reflux for 36 hours. The RM was concentrated in vacuoand the residues purified by chromatography on SiO₂ (Isolute, 50 g),eluting with a gradient 0-10% MeOH/CH₂Cl₂ to give Example 1 as a whitefoam 672 mg(61%).

[0149]¹H NMR (300 MHz, CDCl₃) 0.60-0.80 (m,3H); 1.00-1.20 (m,3H); 1.60(s,6H); 1.80-2.00(m,1H); 2.10-2.30 (m,1H); 2.35 (s,6H); 2.80-3.00(m,2H); 3.10-3.50 (m, 8H); 3.60-3.80 (m,3H); 4.40 (m, 1H)539 ; 6.97(s,1H); 7.00-7.15 (m,3H); 7.20 (s,2H); 7.28-7.36 (m,1H); 7.41 (s,1H);8.22 (s,1H); 8.48-8.60 (m,2H).

[0150] MS (ES⁺) m/z (M+H)⁺ 604.56

[0151] MS (ES⁻) m/z (M−H)⁻ 602.54

[0152] Preparation of Intermediate L

[0153] Diphenyl cyanocarbonimidate (1.5 g, 6.3 mmol) was added to astirred solution of K (1.5 g, 3.7 mmol) in IPA and the mixture stirred18 hours at RT. The RM was concentrated in vacuo and the residuesredissolved in EtOAc (150 ml). The organics were washed with saturatedNaHCO₃ (3×70 ml), brine (2×75 ml), dried (MgSO₄), filtered andevaporated. The crudes were purified by flash chromatography on SiO₂(Merck 9385) eluting with a gradient 0-5% MeOH/CH₂Cl₂ to give L as anoff-white foam 1.9 g(95.4%).

[0154]¹H NMR (300 MHz, CDCl₃) 0.60-0.80 (m,3H); 1.00-1.20 (m,3H);1.55(s,6H); 2.35 (s,6H); 2.75-3.20 (m,2H); 3.10-3.45 (m, 4H); 3.60-3.75(m,2H); 6.30-6.45 (m,1H); 6.67-6.80 (m,2H); 7.00-7.50 (m,9H); 8.18(s,1H).

[0155] MS (ES⁺) m/z (M+H)⁺ 550.36

[0156] MS (ES⁻) m/z (M−H)⁻ 548.30, 454.38

[0157] Preparation of Intermediate K

[0158] n-BuLi (1.6M in Hexanes) (100 ml, 160 mmol) was added dropwise toa stirred, cooled (−78° C.) solution of 5-Bromoxylene (21.73 ml, 160mmol) in THF (235 ml) and Et₂O (235 ml) such that the internaltemperature remained <−65° C. The resulting yellow suspension wasallowed to stir for 1.25 hours before it was added via a cannula to astirred, cooled (−78° C.) solution of—Butyrolactone (14.7 ml, 192 mmol)in THF (180 ml) such that the internal temperature remained <−70° C. Themixture was then stirred at this temperature for a further 5 hours,quenched with saturated NH₄Cl (200 ml) and extracted with Et₂O (3×100ml). The combined organics were washed with brine (2×100 ml), dried(MgSO₄), filtered and concentrated to a yellow oil. This was thenpurified by chromatography on SiO₂ (Merck 9385) eluting with 45%EtOAc/i-Hexane to give G as a pale yellow oil 15.74 g(60%).

[0159]¹H NMR (300 MHz, DMSO-D₆) 1.70 (q,2H); 2.30 (s,6H); 2.98 (t,2H;3.42 (q,2H); 4.43 (t,1H); 7.22 (s,1); 7.52(s, 2H).

[0160] Diethyl Azodicarboxylate (22.5 ml, 143 mmol) was added dropwiseto a stirred, cooled (−5° C.) solution of G (24.0 g, 124 mmol),Phthalimide (20.0 g, 136 mmol) and Triphenylphosphine (36.0 g, 136 mmol)in THF (450 ml) such that the internal temperature remained <0° C. TheRM was stirred for 1 hr at this temperature, diluted with EtOAc (600 ml)and washed with water (250 ml) and brine (250 ml). The organics werethen dried (MgSO₄), filtered and concentrated to a yellow semi-solid.The crudes were purified by chromatography on SiO₂ (Merck 9385) elutingwith 25% EtOAc/i-Hexane to give H as a white powder 13.3 g (34%).

[0161]¹H NMR (300 MHz, DMSO-D₆) 1.80-2.00 (m,2H); 2.28 (s,6H); 3.03(t,2H); 3.62 (t,2H); 7.22 (s,1H); 7.47 (s,2H); 7.70 7.90 (m, 4H).

[0162] BF₃.Et₂O (30 ml) was added to a stirred solution of F (27.0 g, 74mmol) and H (24.4 g, 77 mmol) in AcOH (450 ml) and the resulting mixtureheated at 90° C. for 48 hours. The RM was evaporated to dryness and theresidues treated with saturated NaHCO₃ (100 ml). The resulting solidswere collected by filtration, triturated with MeOH/CHCl₃ andre-filtered. The filtrates were concentrated to give I as an off-whitepowder 36 g (79%).

[0163]¹H NMR (300 MHz, CDCl₃) 0.60-0.75(m,3H); 1.00-1.15 (m,3H); 1.54(s,6H); 2.25 (s,6H); 2.80-2.95 (m,2H); 3.24-3.40 (m,2H); 3.15-3.23 (m,2H); 3.80-3.90 (m,2H); 6.80 (s,1H); 7.06 (s,2H); 7.12 (s,1H); 7.45(s,1H); 7.55-7.70 (m,4H); 8.02 (s,1H).

[0164] LCMS (ES⁺) m/z (M+H)⁺ 613.9, 615.9 (UV 254 nm 100%) p A solutionof I (42.0 g, 68 mmol) in MeOH (1000 ml) and Et₃N (10 ml) was treatedwith 10% Pd/C (10.0 g) and stirred under H₂ (2 Bar) for 48 hours. Thecatalyst was removed by filtration through Celite (545) and thefiltrates evaporated. The residues were redissolved in EtOAc, washedwith water, dried (MgSO₄), filtered and concentrated in vacuo to give Jas a yellow foam 32.2 g (88%).

[0165]¹H NMR (300 MHz, CDCl₃) 0.60-0.80 (m,3H); 1.05-1.25 (m,3H); 1.60(s,6H); 2.30 (s,6H); 2.85-3.05 (m,2H); 3.20-3.50 (m,4H); 3.90-4.00 (m,2H); 6.85 (s,1H); 6.95-7.05 (m,1H); 7.12 (s,2H); 7.20-7.35 (m,1H+CHCl₃);7.55-7.7 (m,3H); 7.70-7.80 (m, 2H); 8.00 (s,1H).

[0166] LCMS (ES⁺) m/z (M+H)⁺ 536.59 (UV 254 nm 100%)

[0167] LCMS (ES⁻) m/z (M−H)⁻ 534.58 (UV 254 nm 100%)

[0168] Hydrazine Hydrate (40 ml, 192 mmol) was added to a stirredsolution of J (28 g, 52.3 mmol) in a mixture of MeOH (200 ml) and CH₂Cl₂(200 ml) and stirred for 48 hours at RT. A further portion of HydrazineHydrate (40 ml) was added and stirring continued for another 24 hours.The RM was filtered, washed with saturated NaHCO₃ (4×150 ml), brine(2×100 ml), dried (MgSO₄), filtered and evaporated. The crudes werepurified by flash chromatography on SiO₂ (Merck 9385) eluting with EtOAcfollowed by 10% MeOH/CH₂Cl₂ to give K as a pale yellow foam 17.1g(80.6%).

[0169]¹H NMR (300 MHz, CDCl₃) 0.60-0.80 (m,3H); 1.05-1.25 (m,3H); 1.60(s,6H); 1.76 (s,2H+H₂O); 2.38 (s,6H); 2.80-3.12 (m,6H); 3.25-3.45 (m,2H); 7.00 (s,1H); 7.02-7.07(m,1H); 7.17 (s,2H); 7.25-7.35 (m,1H); 7.42(s,1H); 8.12 (s,1H).

[0170] LCMS (ES⁺) m/z (M+M)⁺ 406.56 (UV 254 nm 100%)

[0171] LCMS (ES⁻) m/z (M−H)⁻ 404.57 (UV 254 nm 100%)

[0172] Preparation of Intermediate F

[0173] 2N NaOH (510 ml, 1.02 mol) was added to a stirred solution of A(48.5 g, 205 mmol) in MeOH (550 ml) and the resulting mixture heated atreflux for 2 hours. The RM was concentrated, acidified to pH 4 with 2NHCl and extracted with EtOAc (4×200 ml). The combined organics werewashed with brine (3×150 ml), dried (MgSO₄) filtered and evaporated togive B as a cream powder 40.3 g (95%).

[0174]¹H NMR (300 MHz, CDCl₃) 1.66 (s,6H); 7.55 (m,2H); 8.20 (m,2H).

[0175] O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-TetramethyluroniumHexafluoro-Phosphate (89.0 g, 290 mmol) was added portionwise to astirred, cooled (0° C.) solution of B (40.3 g,192 mmol) in DMF (300 ml)and Diethylamine (300 ml). The resulting mixture was left to warm to RTand stir 70 hours. DMF was removed in vacuo and the residues redissolvedin EtOAc (500 ml), washed with water (3×200 ml), brine (2×200 ml), driedMgSO₄, filtered and evaporated.

[0176] The crudes were purified by flash chromatography on SiO₂ (600 g,Merck 9385) eluting with 35% EtOAc/i-Hexane. Appropriate fractions werecombined and evaporated to give C as yellow crystalline solid 44.2 g(87%).

[0177]¹H NMR (300 MHz, CDCl₃) 0.60-0.90 (m, 3H); 0.90-1.25 (m, 3H); 1.58(s,6H); 2.65-2.95 (m, 2H); 3.20-3.45 (m, 2H) ; 7.40 (m, 2H), 8.20 (m,2H).

[0178] LCMS (ES⁺) m/z (M+H)⁺ 265.48 (UV 254 nm 100%)

[0179] A solution of C (89.0 g, 338 mmol) in EtOH (2 L) was treated with10% Pd/C (50% wet) (10.0 g) then stirred under H₂ (3 Bar) at RT for 3hours. The RM was filtered through Celite (545) and evaporated to give Das a tan solid 65.5 g (83%).

[0180]¹H NMR (300 MHz, CDCl₃) 0.60-0.90 (m,3H); 0.90-1.25 (m,3H); 1.48(s,6H); 2.80-3.10 (m,2H); 3.15-3.45 (m,2H); 3.45-3.75 (bs,2H); 6.60-6.70(m,2H); 6.90-7.05 (m, 2H).

[0181] MS (ES⁺) m/z (M+H)⁺ 235.61

[0182] N-Bromosuccinimide (18.24 g, 102.6 mmol) was added portionwise toa stirred, cooled (0° C.) solution of D (24.0 g, 102.6 mmol) in CH₂Cl₂(250 ml) and the mixture stirred for 2 hours. The RM was evaporated, theresidues redissolved in EtOAc (200 ml), washed with saturated NaHCO₃(aq) (3×200 ml), water (2×200 ml), brine (200 ml) , dried MgSO₄,filtered and evaporated. The crudes were purified by flashchromatography on SiO₂ (500 g, Merck 9385) eluting with 5% MeOH/CH₂Cl₂.Appropriate fractions were combined and evaporated to give E as a tansolid 30.4 g (94.7%).

[0183]¹H NMR(300 MHz, CDCl₃) 0.60-0.90 (m,3H); 0.90-1.25 (m,3H); 1.48(s,6); 2.80-3.10 (m,2H); 3.15-3.50 (m,2H); 3.80-4.20 (bs,2H); 6.72(m,1H); 6.95 (m,1H); 7.25 (m, 1H).

[0184] MS (ES⁺) m/z (M+H)⁺ 313.23, 315.26

[0185] A solution of E (15 g, 48 mmol) in cone HCl (48 ml) was cooled to−10° C. and to it was added dropwise a solution of NaNO₂ (3.97 g, 57.5mmol) in water (24 ml) such that the internal temperature remained <−8°C. The resulting solution was left to stir for 1 hr at this temperaturebefore it was added dropwise to a solution of SnCl₂.2H₂O (53.0 g, 235mmol) in conc HCl (36.5 ml) at −12° C. such that the internaltemperature remained <−10° C. The mixture was stirred for 2 hours at−10° C. then allowed to warm to 10° C. before it was quenched into water(600 ml), neutralised with solid NaHCO₃, filtered and extracted withEtOAc (3×400 ml). The organics were dried (MgSO₄), filtered andevaporated to a yellow oil. This was treated with 1M HCl/Et₂O and driedto give the HCl salt of F as a free flowing white powder 14.7 g (84.4%)

[0186]¹H NMR (300 MHz, DMSO-D₆) 0.50-0.85 (m,3H); 0.85-1.10 (m,3H); 1.40(s,6H); 2.70-3.00 (m,2H); 3.00-3.40(m,2H); 7.00-7.10 (m,1H);7.10-7.20(m, 1H); 7.20-7.30 (m,1H).

[0187] LCMS (ES⁺) m/z (M+H)⁺ 328.3, 330.3 (UV 254 nm 95%)

[0188] Following a procedure similar to that described in Example 1, theexamples 1.01 to 1.30 were prepared. STRUCTURE EXAMPLE MS (ES)+

1.01 578.74(M + H)+

1.02 592.44(M + H)+

1.03 606.76(M + H)+

1.04 578.72(M + H)+

1.05 592.74(M + H)+

1.06 583.70(M + H)+

1.07 584.79(M + H)+

1.08 567.74(M + H)+

1.09 582.74(M + H)+

1.10 598.71(M + H)+

1.11 648.99(M + H)+

1.12 598.86(M + H)+

1.13 656.84(M + H)+

1.14 613.93(M + H)+

1.15 600.89(M + H)+

1.16 586.85(M + H)+

1.17 578.7(M + H)+

1.18 585.83(M + H)+

1.19 584.87(M + H)+

1.20 584.54(M + H)+

1.21 592.53(M + H)+

1.22 618.55(M + H)+

1.23 604.6(M + H)+

1.24 604.54(M + H)+

1.25 590.76(M + H)+

1.26 596.78(M + H)+

1.27 618.58(M + H)+

1.28 639.73(M + H)+

1.29 617.55(M + H)⁺

1.30 632.52(M + H)⁺

Example 2

[0189]

[0190] 4-Pyrrolidin-3-yl pyridine (148 mg, 1.00 mmol) was added to astirred suspension of M (105 mg, 0.20 mmol) in IPA (5 ml) and themixture heated at reflux for 48 hours. The RM was concentrated in vacuoand the residues purified by chromatography on SiO₂ (Isolute, 50 g),eluting with a gradient 0-20% MeOH/EtOAc to give 2 as a tan foam 71.0mg(57%).

[0191]¹H NMR (300 MHz, CDCl₃) 0.45-0.65 (m,3H); 0.85-1.05 (m,3H); 1.45(d,6H); 1.70-1.90 (m,1H); 2.00-2.20 (m,1H); 2.20 (s,6H); 2.60-2.90(m,2H); 3.00-3.30 (m, 8H); 3.30-3.50 (m,3H); 6.28 (s,1H); 6.80-7.00(m,6H); 7.10-7.25 (m,2H); 8.05 (s,1H); 8.37 (d,2H); 9.90 (t,1H).

[0192] MS (ES⁺) m/z (M+H)⁺ 623.28

[0193] MS (ES⁻) m/z (M−H)⁻ 621.23

[0194] Preparation of Intermediate M

[0195] 1,1 Bis(methylthio)-2-nitroethylene (515 mg,3.1 mmol) was addedto a stirred solution of K (1.1 g, 2.72 mmol) in CH₃CN (70 ml) andheated at reflux for 18 hours. The RM was concentrated in-vacuo and thecrudes purified by chromatography on SiO₂ (Merck 9385), eluting with 5%MeOH/CH₂Cl₂ to give M as a yellow foam 1.4 g(98%).

[0196]¹H NMR (300 MHz, CDCl₃) 0.60-0.80 (m,3H); 1.05-1.25 (m,3H); 1.60(s,6H); 2.38(s,6H); 2.80-3.05 (m,2H); 3.25-3.50 (m, 4H); 3.68 (q,2H);6.42 (s,1H); 7.05 (s,1H); 7.06-7.15 (m,3H); 7.32 (d,1H); 7.45 (s,1H);8.11 (s,1H).

[0197] MS (ES⁺) m/z (M+H)⁺ 523.44

[0198] MS (ES⁻) m/z (M−H)⁻ 521.49

[0199] Following a procedure similar to that described in Example 2, thefollowing compound was prepared. STRUCTURE EXAMPLE MS (ES)+

2.01 597.57(M + H)+

Example 3

[0200]

[0201] A solution of K (see Example 1) (100 mg, 0.25 mmol) andDiisopropyl ethylamine (36.0 mg,0.25 mmol) in CH₂Cl₂ (1 ml) was added toa solution of Triphosgene (29.7 mg, 0.10 mmol) in CH₂Cl₂ (1 ml) and themixture stirred for 15 minutes. A solution of Diisopropylethylamine(36.0 mg, 0.25 mmol) and 4-Pyrrolidin-3-yl pyridine (37.0 mg,0.25 mmol)in CH₂Cl₂ (1 ml) was added and the mixture stirred for 60 hours. The RMwas concentrated in-vacuo and the residues purified by chromatography onSiO₂ (Isolute, 50 g), eluting with a gradient 0-10% MeOH/CH₂Cl₂ to giveExample 3 as a pale yellow foam 88.0 mg(60%).

[0202]¹H NMR (300 MHz, CDCl₃) 0.60-0.80 (m,3H); 1.00-1.30 (m,3H); 1.60(s,6H); 1.80-2.00 (m,1H); 2.15-2.30 (m,1H); 2.35 (s,6H); 2.80-3.00(m,2H); 3.05-3.45 (m, 8H); 3.50-3.70 (m,3H); 4.20 (m,1H); 6.85 (s,1H);7.00-7.10 (m,3H); 7.22 (s,2H); 7.30 (d,1H); 7.45 (d,1H); 8.12 (s,1H);8.50 (d,2H).

[0203] MS (ES⁺) m/z (M+H)⁺ 580.72

[0204] MS (ES⁻) m/z (M−H)⁻ 578.77

[0205] Following a procedure similar to that described in Example 3,examples 3.01 to 3.06 were prepared. STRUCTURE EXAMPLE MS (ES)+

3.01 559.56(M + H)+

3.02 582.3(M + H)+

3.03 568.71(M + H)+

3.04 554.68(M + H)+

3.05 540.68(M + H)+

3.06 553.38(M + H)+

Example 4

[0206]

[0207] 2N HCl (5 ml) was added to a stirred solution of Example 1 (150mg, 0.22 mmol) in MeOH (5 ml) the resulting mixture was heated at 60° C.for 18 hours. The RM was evaporated to dryness and the residuespartitioned between saturated NaHCO₃ (100 ml) and EtOAc (3×25 ml).Combined organics were concentrated in vacuo and the crudes purified byflash chromatography on SiO₂ (Isolute, 50 g), eluting a gradient 0-25%MeOH/CH₂Cl₂ to give Example 4 as a white solid 55.6 mg (38.0%).

[0208]¹H NMR (300 MHz, DMSO-D₆) 0.50-0.80 (m,3H); 0.90-1.10 (m,3H); 1.45(s,6H); 1.80-2.10 (m,1H); 2.20-2.40 (m,1); 2.30 (s,6H); 2.70-2.95(m,2H); 3.05-3.55 (m, 10H); 3.55-3.70 (m,1H); 6.90 (s,1H); 7.00 (s,1H);7.15-7.45 (m,7H); 7.50 (s,2H); 8.50 (d,2H); 11.15 (s,1H).

[0209] MS (ES⁺) m/z (M+H)⁺ 579.5

[0210] MS (ES⁻) m/z (M−H)⁻ 577.6

[0211] Following a procedure similar to that described in Example 4, theexamples 4.01 to 4.05 were prepared. MS ¹H NMR (300MHz, DMSO- STRUCTURE(ES)+ D₆ + CD₃COOD) 4.01

577.36 (M + H)⁺575.37 (M − H)⁻ δ1.3-1.7(m, 10H); 1.80-2.05(m, 1H);2.2-2.4(m, 7H); 2.6-2.8(m, 2H); 3.0-3.5(m, 10H); 3.6(t, 1H); 6.9(d, 1H);6.95(s, 1H); 7.15-7.35(m, 5H); 7.38(s, 1H); 8.5(d, 2H). 4.02

603.43 (M + H)⁺601.35 (M − H)⁻ δ1.3-1.7(m, 14H); 1.80-2.05(m, 1H);2.2-2.4(m, 7H); 3.0-3.6(m, 10H); 3.65(t, 1H); 6.9-7.05(m, 2H);7.12-7.35(m, 5H); 7.4(s, 1H); 8.5(d, 2H). 4.03

591.34 (M + H)⁺589.36 (M − H)⁻ δ1.25-1.65(m, 10H); 1.7-1.9(m, 2H);1.9-2.1(m, 1H); 2.1-2.4(m, 7H); 2.55-2.75(m, 2H); 2.88(t, 2H); 3.15(t,2H); 3.2-3.6(m, 6H); 3.7(t, 1H); 6.9(d, 1H); 6.95(s, 1H); 7.15(s, 2H);7.2-7.4(m, 4H); 8.5(d, 2H). 4.04

615(M − NMR (400Mz, 373° K, DMSO-d6) δ1.19(m, 4H); 1.35(m, 4H); 1.43(d,3H); 1.53(d, 6H); 2.00(m, 1H); 2.33(m, 7H); 3.25-3.73(m, 8H); 4.08(s,2H); 6.94(broad s, 1H); 6.98 & 7.03(2m, 1H); 7.06(d of d, 1H); 7.14(s,2H); 7.22(m, 3H); 7.30 & 7.34(2d, 1H); 7.49 & 7.51(2m, 1H); 8.47 &8.51(2d, 2H); 10.68 & 10.80(2s, 1H). 4.05

629 (M − H)⁻ NMR(400Mz, 373° K, DMSO-d6) δ1.12-1.47(m, 9H); 1.50(m, 7H);2.00(m, 1H); 2.32(m, 7H); 3.15-3.74(complex, 13H); 6.84-7.04 (complex,3H); 7.14(s, 2H); 7.21 (m, 3H); 7.29 & 7.33(2d, 1H); 7.43 & 7.45(2s,1H); 8.47 & 8.51(2d, 2H); 10.64 & 10.76(2s, 1H).

Example 5

[0212]

[0213] 4-Pyrrolidin-3-yl pyridine (1.48 g, 10 mmol) was added to astirred suspension of Q (1.0 g, 2 mmol) in IPA (50 mL) and the mixtureheated at reflux for 18 hrs. The RM was concentrated in vacuo and theresidues purified by chromatography on SiO₂ (Isolute, 50 g), elutingwith a gradient 0-10% MeOH/CH₂Cl₂ to give Example 5 as a white foam 860mg(71%).

[0214]¹H NMR (300 MHz, CDCl₃) δ1.45-1.8 (m,10H+H₂O); 1.80-2.00(m,1H);2.16-2.30 (m,1H); 2.35 (s,6H); 2.7-2.84(m,2H); 3.20-3.80 (m, 11H);4.46-4.56 (m,1H); 6.92-7.48 (m,8H); 8.37 (s,1H); 8.48-8.60 (m,2H).

[0215] MS (ES⁺) m/z (M+H)⁺ 602.34

[0216] MS (ES⁻) m/z (M−H)⁻ 600.33

[0217] Preparation of Intermediate Q

[0218] P was treated with Diphenyl cyanocarbonimidate analogously as forthe preparation of L (see Example 1)to give Q.

[0219] MS (ES⁺) m/z (M+H)⁺ 548.28

[0220] MS (ES⁻) m/z (M−H)⁻ 546.27

[0221] Preparation of Intermediate P

[0222] O was treated with the ketone H and deprotected analogously asfor the preparation of K (see Example 1) to give P.

[0223]¹H NMR (300 MHz, DMSO-D₆+CD₃COOD) δ1.3-1.7 (m, 10H); 2.35 (s,6);2.6-2.74 (m,2H); 2.9-3.2 (m,4H); 3.26-3.42 (m,2H); 6.88-6.94 (m,1H);7.02 (s,1H); 7.18 (s,2H); 7.3 (s,1H); 7.42 (s,1H).

[0224] MS (ES⁺) m/z (M+H)⁺ 404.33

[0225] MS (ES⁻) m/z (M−H)⁻ 402.32

[0226] Preparaton of Intermediate O

[0227] A solution of Ethyl 2-(4-amino-3-bromophenyl)-2-methylpropionate(L) (100 g, 349.6 mmol) in MeOH (400 mL) was treated with 2N NaOH (300mL, 600 mmol) and the mixture refluxed 18 hrs. The RM was evaporated todryness and the residues redissolved in water (200 mL).

[0228] The pH was adusted to 4 with 2N HCl (aq) and the aqueous wasextracted with EtOAc (3×200 mL). The combined organics were washed withbrine (2×100 mL), dried (MgSO₄), filtered and evaporated to give M as acrystalline solid 86 g (95%).

[0229]¹H NMR (300 MHz, CDCl₃) δ1.55 (s,6H); 6.70-6.75 (d,1H); 7.1-7.16(dd,1H); 7.46 (s,1H).

[0230] MS (ES⁺) m/z (M)⁺ 258.48

[0231] TBTU (1.37 g, 4.268 mmol) was added to a stirred solution of M(1.0 g, 3.87 mmol), pyrrolidine (646 μL, 7.75 mmol) and DIPEA (1.35 mL,7.75 mmol) in CH₂Cl₂ (50 mL). The resulting solution was left to stir 64hrs then washed with water (25 mL). The aqueous was extracted withCH₂Cl₂ (25 mL) and the combined organics were dried (MgSO₄), filteredand evaporated to a yellow solid. The crudes were purified by flashchromatography on SiO₂ (Isolute, 50 g). Eluting with a gradient 0-50%EtOAc/CH₂Cl₂ to give N as a white crystalline solid 1.17 g (96.7%).

[0232]¹H NMR (300 MHz, CDCl₃) δ1.55 (s,6H); 1.55-1.8 (m,4H+H₂O); 2.8(t,2H); 3.5 (t,2H); 4.02 (s,2H); 6.70(d,1H); 6.99 (dd,1H); 7.3 (d,1H).

[0233] MS (ES⁺) m/z (M+H)⁺ 313.08

[0234] N (15.23 g, 48.8 mmol) was diazotised and reduced malogously asfor F (see Example 1) to give the HCl salt, O as a white powder 12.83g(73%).

[0235]¹H NMR (300 MHz, DMSO-D₆+CD₃COOD) δ1.4 (s,6H); 1.3-1.7 (m,4H);2.6-2.85 (m,2H); 3.2-3.45 (m,2H); 7.0 (d,1H); 7.15 (dd,1H); 7.33 (d,1H).

[0236] MS (ES⁺) m/z (M+H)⁺ 327.98

[0237] Following a procedure similar to that described in Example 5, theexamples 5.01 to 5.06 were prepared. STRUC- MS TURE (ES)+ ¹H NMR(300MHz, CDCl₃) 5.01

602.19 δ 1.4-1.8(m, 10H + H₂O); 1.80-2.00(m, 1H); 2.15-2.35(m, 1H);2.35(s, 6H); 2.75(t, 2H); 3.15-3.60(m, 8H); 3.6-3.75(m, 3H); 4.45(t,1H); 6.95(s,1H); 7.08(dd, 1H); 7.2(s, 2H); 7.2-7.4(m, 2H); 7.4-7.5(m,2H); 8.3(s, 1H); 8.48(s, 1H); 8.5(d, 1H). 5.02

602.35 (M + H)⁺ δ 1.4-1.9(m, 12H + H₂O); 2.1-2.3(m, 1H); 2.4(s, 6H);2.75(t, 2H; 3.1-3.2(m, 2H); 3.38-3.65(m, 6H); 3.7-3.9(m, 1H); 4.3(t,1H); 4.6-4.8(m, 1H); 6.72(d, 2H); 7.02(s, 1H); 7.05-7.15(m, 3H); 7.35(d,1H); 7.42(s, 1H); 8.25(s, 1H); 8.4(d, 2H). 5.03

602.36 (M + H)⁺ δ 1.4-1.8(m, 10H + H₂O); 1.8-2.1(m, 2H); 2.1-2.35(m,1H); 2.4(s, 6H); 2.75(t, 2H); 3.05(t, 2H); 3.4-3.8(m, 7H); 4.7-4.85(m,1H); 5.4-5.5(m, 1H); 6.98-7.2(m, 6H); 7.3(d, 1H); 7.45(s, 1H); 7.6(t,1H); 8.1(s, 1H); 8.2-8.3(m, 1H). 5.04

631.33 (M + H)⁺ δ 1.4-1.8(m, 10H + H₂O); 2.2-2.4(m, 10H); 2.75(t, 2H);3.1-3.2(m, 4H); 3.25(t, 2H); 3.45(s, 2H); 3.45-3.6(m, 2H); 3.6-3.75(m,2H); 4.4-4.65(m, 1H); 6.98(s, 1H); 7.08(d, 1H); 7.17(s, 2H); 7.21(d,2H); 7.32(d, 1H); 7.45(s, 1H); 8.28(s, 1H); 8.55(d, 2H). 5.05

642 (M + H)⁺ NMR (400Mz, 373° K, DMSO-d6) δ 1.17(m, 5H); 1.35(m, 6H);1.50(d, 6H); 1.95(m, 1H); 2.27(m, 1H); 2.33(s, 6H); 3.33-3.83(complex,8H); 4.11(s, 2H); 6.42(s, 1H); 7.01(m, 2H); 7.17(s, 2H); 7.21(d of d,2H); 7.30(d, 1H); 7.54(s, 1H); 8.48(d of d, 2H; 10.78(s, 1H). 5.06

656 (M + H)⁺ NMR (400Mz, 373° K, DMSO-d6) δ1.15-1.47(m, 10H); 1.50(d,6H), 1.95(m, 1H); 2.28(m, 1H); 2.33(s, 6H); 3.13-385(complex, 13H);6.40(s, 1H); 6.94(d, 1H); 6.99(s, 1H); 7.17(s, 2H); 7.21(d, 2H); 7.30(d,1H); 7.48(s, 1H); 8.48(d, 2H); 10.79(s, 1H).

Example 6

[0238]

[0239] 4-Pyrrolidin-3-yl pyridine (607 mg, 4.1 mmol) was added to astirred suspension of R (472 mg, 0.82 mmol) in IPA (50 mL) and themixture heated at reflux for 18 hrs. The RM was concentrated in vacuoand the residues purified by chromatography on SiO₂ (Isolute, 50 g),eluting with a gradient 0-10% MeOH/CH₂Cl₂ to give Example 6 as a whitefoam 314 mg(61%).

[0240]¹H NMR (300 MHz, CDCl₃) δ1.0-1.5 (m,8H); 1.6 (s,6H);1.85-2.00(m,1H); 2.2-2.35 (m,1H); 2.38 (s,6H); 3.20-3.55 (m, 6H);3.6-3.8 (m,4H); 4.42-4.52 (m, 1H); 4.6-4.8 (bm,1H); 7.0 (s,1H); 7.07(d,2H); 7.12-7.2 (m,1H); 7.24 (s,2H); 7.33 (d,1H); 7.48 (s,1H); 8.23(s,1H); 8.54-8.58 (m,2H).

[0241] MS (ES⁺) m/z (M+H)⁺ 628.42

[0242] MS (ES⁻) m/z (M−H)⁻ 626.43

[0243] Preparation of Intermediate R

[0244] 7-Azabicyclo[2.2.1]heptane,7-[2-[3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methyl-1-oxopropyl]-(9CI)(350 mg, 0.815 mmol) was coupled with Diphenyl cyanocarbonimidateanalogously as for the preparation of L (see Example 1) to give R,.

[0245]¹H NMR (300 MHz, CDCl₃) δ1.0-1.45 (m,8H); 1.6 (s,6H); 2.35 (s,6H);3.10-3.30 (m,2H); 3.5-3.64 (m,1H); 3.64-3.8 (m,2H); 4.6-4.8 (m,1H),6.14-6.22(m,1H); 6.74-6.82 (d,1H); 7.05 (s,1H); 7.08-7.14 (d,1H); 7.16(s,2H); 7.2-7.45 (m,5H); 7.5 (s,1H); 8.14 (s,1H).

[0246] MS (ES⁺) m/z (M+H)⁺ 628.42

[0247] MS (ES⁻) m/z (M−H)⁻ 626.43

Example 7

[0248]

[0249] 7-Azabicyclo[2.2.1]heptane,7-[2-[3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methyl-1-oxopropyl]-(9CI)(215 mg, 0.5 mmol) was coupled with 4-Pyrrolidin-3-yl pyridine under thesame conditions employed in Example 3 to give Example 7 as a colourlessfoam, 24 mg (8%).

[0250]¹H NMR (300 MHz, CDCl₃) δ1.0-1.5 (m,8H); 1.6 (s,6H);1.5-1.7(m,2H); 1.8-2.0(m,1H); 2.2-2.35 (m,1H); 2.36 (s,6H); 3.10-3.8(m,8H); 4.24-4.32 (t,1H); 4.6-4.8 (m,1H); 6.96 (s,1H); 7.06-7.12 (m,2H);7.14 (s,1H) 7.22 (s,2H); 7.3-7.34 (d,1H); 7.52 (s,1H); 8.23 (s,1H);8.4-8.6 (m,2H).

[0251] MS (ES⁺) m/z (M+H)⁺ 604.36

[0252] MS (ES⁻) m/z (M−H)⁻ 602.44

Example 8

[0253]

[0254]2-Azabicyclo[2.2.2]octane,2-[2-[3-[(1S)-2-amino-1-methylethyl]-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methyl-1-oxopropyl]-(9CI)(250 mg, 0.547 ml) was coupled with 4-Pyrrolidin-3-yl pyridine under thesame conditions employed in Example 3 to give Example 8 as a white foam,99 mg (28%).

[0255]¹H NMR (300 MHz, CDCl₃) δ1.0-1.75 (m,17H); 1.75-2.0 (m,2H);2.1-2.4 (m,1H); 2.35 (s,6H); 3.05-3.55 (m,9H); 3.55-3.7 (m,1H); 3.7-3.9(m,1H); 4.05-4.2 (m,1H); 6.9-7.2 (m,6H); 7.33 (d, 1H); 7.52 (s,1H); 8.06(s,1H); 8.4-8.6 (m,2H).

[0256] MS (ES⁺) m/z (M+H)⁺ 632.23

[0257] MS (ES⁻) m/z (M−H)⁻ 630.20

Example 9

[0258]

[0259] A solution of 7-Azabicyclo[2.2.1]heptane,7-[2-[3-[(1S)-2-amino-1-methylethyl]-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methyl-1-oxopropyl]-(9CI)(150 mg, 0.338 mmol) in CH₂Cl₂ (5 mL) was treated with2,6-Dichloro-pyridin-4-Yl isocyanate (70 mg, 0.37 mmol) and theresulting mixture left to stir for 18 hrs. The RM was purified by flashchromatography on SiO₂ (Varian, 20 g), eluting with a gradient 0-50%EtOAc/CH₂Cl₂ to give Example 9 as a white foam 120 mg(56%).

[0260]¹H NMR (300 MHz, CDCl₃) δ1.0-1.8 (m,17H); 2.35 (s,6H); 3.5-3.65(m,3H); 3.65-3.8 (m,1H); 4.4-4.6 (m,1H); 5.8-5.95 (m,1H); 7.0 (s,1H);7.05 (d,1H); 7.15 (s,2H); 7.2-7.5 (m,4H); 8.05 (s,1H); 8.6-8. (bs,1H).

[0261] MS (ES⁺) m/z (M+H)⁺ 632.08

[0262] MS (ES⁻) m/z (M−H)⁻ 630.12

Example 10

[0263]

[0264] A mixture of Example 9 (100 mg, 0.158 mmol) and 10% Pd/C (30 mg)in MeOH (5 mL) and Et₃N (1mL) was stirred under an atmosphere of H₂ for18 hrs. The mixture was filtered evaporated and the crudes were purifiedby flash chromatography on SiO₂ (Varian, 20 g), eluting with a gradient0-10% MeOH/CH₂Cl₂ to give Example 10 as a white foam, 56.4 mg (63.2%).

[0265]¹H NMR (300 MHz, CDCl₃) δ1.0-1.7 (m,14H); 1.75 (s,3H); 2.35(s,6H); 3.4-3.8 (m,4H); 4.4-4.6 (m,1H); 5.8-5.90 (m,1H); 6.95 (s,1H);7.05 (d,1H); 7.12 (s,2H); 7.2-7.35 (m,3H); 7.5 (s,1H); 8.18 (d,2H); 8.3(bs,1H); 8.35 (bs,1H).

[0266] MS (ES⁺) m/z (M+H)⁺ 564.49

[0267] MS (ES⁻) m/z (M−H)⁻ 562.22

Example 11

[0268]

[0269] Intermediate X (675 mg, 1.2 mmol) was treated with4-Pyrrolidin-3-yl pyridine analogously as for Example 8 to give Example11 as a white foam 576.4 mg(78%).

[0270]¹H NMR (300 MHz, CDCl₃) δ1.45-1.8 (m,10H); 1.85-2.1(m,3H);2.2-2.45 (m,7H); 2.8 (t,2H); 3.0 (t,2H); 3.0-3.70 (m, 9H); 4.35 (t,1H);6.9 (s,1H); 6.95-7.13(m,3H); 7.17 (s,2H); 7.25(d,1H); 7.44 (s,1H); 8.32(s,1H); 8.55 (d,2H).

[0271] MS (ES⁺) m/z (M+H)⁺ 616.73

[0272] MS (ES⁻) m/z (M−H)⁻ 614.74

[0273] Preparation of Intermediate X

[0274] δ-Valerolactone was modified analogously as for the preparationof Q (see Example 5) to give the homologous tryptamine derivative X.

[0275]¹H NMR (300 MHz, CDCl₃) δ1.45-1.58 (m,2H); 1.59-1.73 (m,8H);1.95-2,1 (m,2H); 2.38 (s,6H); 2.70-2.84 (m,2H); 2.88-3.10 (m,2H);3.25-3.5 (m,2H); 3.5-3.6 (m,2H); 6.3-6.42 (m,1H); 6.90-7.50 (m,11H);8.20 (s,1H).

[0276] MS (ES⁺) m/z (M+H)⁺ 562.50

[0277] MS (ES⁻) m/z (M−H)⁻ 560.51

[0278] Following a procedure similar to that described in Example 11,the example 11.01 was prepared. MS STRUCTURE (ES)+ ¹H NMR(300MHz, CDCl₃)11.01

616.75 (M + H)⁺614.77 (M − H)⁻ δ 1.4-2.0(m, 15H); 2.2-2.50(m, 7H);2.7-3.0(m, 4H); 3.25-3.65(m, 6H); 4.35(t, 1H); 4.80-4.95(m, 1H); 6.95(d,2H); 7.05(s, 1H); 7.10(dd, 1H); 7.15(d, 2H); 7.33(d, 1H); 7.4(s, 1H);8.25(s, 1H); 8.45(d, 2H).

Example 12

[0279]

[0280] Intermediate DD (70.9 mg, 0.13 mmols) and Intermediate CC (53.8mg, 0.26 mmols) were suspended in iso-propanol (5 ml). Triethylamine(0.06 ml, 0.43 mmols) was added and the reaction mixture was heated to90° C. for 3 days. The reaction mixture was allowed to cool thenconcentrated in vacuo. The residue was purified by Prep LCMS to givecompound 5 (9.2 mg 0.01 mmols) as a white solid.

[0281] Mass spectrum:[MH]⁺=622.46 [M−H]⁻=620.33

[0282]¹H NMR −300 MHz, CDCl₃ δ(ppm); −8.14 (1H, s); 7.46 (1H, s);7.32-7.30 (1H, d); 7.21 (2H, s); 7.09-7.07 (1H, d); 7.00 (1H, s); 6.78(1H, s); 4.44-4.37 (1H, m); 3.71-3.61 (4H, m); 3.59-3.47 (4H, m);3.44-3.36 (2H, m); 3.29-3.22 (2H, m); 2.82-2.74 (2H, m); 2.40 (3H, s);2.37 (6H, s); 1.73-1.65 (2H, m); 1.60 (6H, s); 1.57-1.51 (2H, m)

[0283] Preparation of Intermediate DD

[0284] Intermediate DD was prepared using a method analogous to thepreparation of Intermediate X (see Example 11).

[0285] Preparation of Intermediate CC

[0286] Intermediate BB (0.43 g, 1.6 mmols) was dissolved in 1,4-dioxane(40 ml). 4M HCl in dioxane (2 ml, 8 mmols) was added. The reactionmixture was stirred at room temperate under a nitrogen atmosphere for 2days. More 4M HCl in dioxane (2 ml, 8 mmols) was added and after stingat room temperature for a further 3.5 days the reaction mixture wasconcentrated in vacuo. Ether was added to the residue. The ether wasremoved under reduced pressure and the resulting gum was azetroped withtoluene (×3). The resulting solid was dried in a desiccator to giveIntermediate CC (0.32 g, 1.57 mmols) as the HCl salt.

[0287] Mass Spectrum:[MH]⁺=169.14

[0288] 1H NMR −300 Mz, d₆-DMSO+d₄-acetic acid δ(ppm): −7.20 (1H, s),3.95-3.83 (1H, m), 3.65-3.54 (1H, m); 3.37-3.20 (4H, m); 2.44-2.36 (1H,m); 2.33 (3H, s); 2.13-2.03 (1H, m)

[0289] Preparation of Intermediate BB

[0290] Intermediate AA (0.97 g, 4.2 mmols) was dissolved in ethanol (35ml). Chloroacetone (0.4 ml, 5.0 mmols) was added and the reactionmixture heated to reflux. After 7 hours the reaction mixture was allowedto cool and concentrated in vacuo. The residue was taken up in a mixtureof dichloromethane and water. The organic phase was removed, washed withwater, dried (MgSO₄), filtered and concentrated in vacuo to giveIntermediate BB (0.43 g, 1.6 mmols).

[0291] Mass Spectrum:mass ion not observed

[0292] 1H NMR −300 MHz, d₆-DMSO δ(ppm):−7.12 (1H, s); 3.78-3.64 (2H, m);3.45-3.32 (1H, m); 2.31 (3H, s); 2.28-2.20 (2H, m), 2.11-1.93 (2H, m);1.39 (9H, m)

[0293] Preparation of Intermediate AA

[0294] For the synthesis of Intermediate AA the reader is referred toJournal of Medicinal Chemistry., 1990, Volume 33, Page 2052

Example 13

[0295]

[0296] Example 13 was prepared using a method analogous to Example 12.

Example 14

[0297]

[0298] A mixture of Intermediate EE (0.66 grms),3-(4-pyridyl-pyrrolidine)(0.9 grms) and triethylamine(1 ml.) iniso-propanol(40 mls.) was stirred and heated at 90 degs. for 48 hours.The reaction was cooled and evaporated to dryness. The residue waspurified by flash column chromatography on silica eluting withmethanol/dichloromethane(1:20 and 1:10) to give Example 14 as a paleyellow foam(0.21 grms.).

[0299]¹H NMR (d-6-DMSO, δ values) 1.29-1.69 (m, 6H); 1.47 (d, 6H);1.75-2,40(m, 4H); 2.30 (d, 6H); 2.60-2.85 (m, 2H); 2.95-3.90 (m, 12H);6.87 (m, 1H); 7.00 (d, 1H); 7.10 (s, 1H); 7.14 (s, 1H); 7.21-7.35(m,3H); 7.50 (d, 1H); 8.46 (d, 2H); 11.11 & 11.14 (2br.s, 1H).

[0300] MS(ES⁺) m/z (M+H)⁺ 642.56

[0301] Preparation of Intermediate II

[0302] A solution of lithium diisopropylamide(31 mls, 2M in THF) wasadded dropwise to a stirred solution of 3-picoline (5.7 grms.) inTHF(100 mls.) cooled to 0 degs. under a nitrogen atmosphere. After 30mins. at this temperature a solution of methyl 3,5-dimethylbenzoate(5grms.) in THF(20 mls.) was added maintaining the temperature below 0degs. during the addition and for 1 hour afterwards. The reaction wasquenched with saturated ammonium chloride(100 mls.) and extracted withethyl acetate. The extracts were dried and evaporated to dryness. Theresidue was purified by flash column chromatography on silica elutingwith ethyl acetate/iso-hexane(1:1) to give Intermediate EE as a yellowoil which slowly crystallized(3.2 grms).

[0303]¹H NMR (d-6-DMSO, δ values) 2.33 (s, 6H); 4.41 (s, 2H); 7.25-7.37(m, 2H); 7.6-7.7 (m, 3H); 8.42 (m, 2H).

[0304] MS(ES⁺) m/z (M+H)⁺ 226.02

[0305] A mixture of Intermediate EE (3.0 grms.), Intermediate O (seeExample 5)(5.8 grms.), glacial acetic acid(50 mls,) and borontrifluoride diethyl etherate(5 mls.) was stirred and heated at 95-100degs. for 18 hours under a nitrogen atmosphere. The reaction mixture wascooled and the acetic acid was evaporated away. The residue was basifiedwith saturated sodium bicarbonate solution and extracted with ethylacetate. The extracts were dried, evaporated to dryness and the residuepurified by flash column chromatography on silica eluting with ethylacetate/iso-hexane(1:1, 4:1) and ethyl acetate to give Intermediate FF(5.00 grms.) as a yellowish solid.

[0306]¹H NMR (d-6-DMSO, δ values) 1.35-1.69 (m, 4H); 1.40 (s, 6H); 2.2(s, 6H); 2.64-2.8 (m, 2H); 3.21-3.40 (m, 2H); 6.98 (s, 1H); 7.03 (s,2H); 7.14 (s, 1H); 7.27 (s, 1H); 7.35-7.44 (m, 1H); 7.66 (d, 1H);8.40-8.50 (m, 2H); 11.63 (br.s, 1H).

[0307] MS(ES⁺) m/z (M+H)⁺ 515.97, 517.96

[0308] A mixture of Intermediate FF (5.00 grms.) and 10% palladium oncarbon(1.3 grms.) in methanol(200 mls.) was stirred under an atmosphereof hydrogen for 18 hours. The reaction was filtered and the filtrateevaporated to dryness, basified with saturated sodium bicarbonate andextracted with ethyl acetate, the extracts dried and evaporated to giveIntermediate GG as a white solid(3.9 grms.).

[0309]¹H NMR (d-6-DMSO, δ values) 1.36-1.70 (m, 4H); 1.46 (s, 6H); 2.23(s, 6H); 2.70 (m, 2H); 3.35 (m, 2H); 6.95-7.10 (m, 4H); 7.43 (m, 2H);7.91 (m, 1H); 8.29 (d, 1H); 8.7 (m, 2H); 11.85 (br.s, 1H).

[0310] MS(ES⁺) m/z (M+H)⁺ 438.03

[0311] A mixture of Intermediate GG (3.5 grms.) and platinum oxide(800mgs.) was stirred under an atmosphere of hydrogen for 8 hours. Thecatalyst was filtered off and the filtrate evaporated to dryness to givea white solid. Recrystallisation from ethyl acetate gave the startingmaterial(0.45 grms.). The mother liquors were evaporated to give (5) asa white solid(2.9 grms.). This was converted to the hydrochloride saltby addition of ethereal HCl to a solution of Intermediate HH in ethylacetate and the solid isolated by centrifugation.

[0312]¹H NMR (d-6-DMSO, δ values) 1.32-2.00 (m, 7H); 1.50 (d, 6H);2.00-2.10 (m, 1H); 2.36 (s, 6H); 2.62-2.80 (m, 2H); 2.90-3.11 (m, 1H);3.20-3.48 (m, 6H); 6.89 (d, 1H); 7.05 (s, 1H); 7.10 (s, 2H); 7.30 (d,1H).); 7.58 (s, 1H); 8.83 (br.s, 2H); 11.20 (br.s, 1H).

[0313] MS(ES⁺) m/z (M+H)⁺ 444.04

[0314] A mixture of Intermediate HH (0.5 grms.), diphenylcyano-carbonimidate(0.45 grms.) in iso-propanol(50 mls.) was stirred atambient temperature for 18 hours. It was then evaporated to dryness andthe residue purified by flash column chromatography on a silica columneluting with ethyl acetate/iso-hexane(4:1) to give Intermediate II as awhite foam(0.66 grms.).

[0315]¹H NMR (d-6-DMSO, δ values) 1.20-1.72 (m, 8H); 1.49 (s, 6H);1.88(m, 2H); 2.13-2.60 (m, 2H); 2.34 (s, 6H); 2.70 (m, 2H); 3.34 (m,2H); 3.65 (m, 1H); 6.72 (m, 3); 6.85 (m, 1H); 7.00-7.60(m, 7H); 11.16(br.s, 1H).

[0316] MS(ES⁺) m/z (M+H)⁺ 5.58

Example 15

[0317]

[0318] By a method analogous to Example 14, Example 15 was prepared fromIntermediate II (see Example 14) using 4-aminoethylpyridine instead of3-(4-pyridyl-pyrrolidine).

[0319]¹H NMR (d-6-DMSO, δ values) 1.32-1.53 (m, 6H); 1.49 (s, 6H);1.53-1.89(m, 4H); 2.00-2.20 (m, 1H); 2.33 (s, 6H); 2.70 (m, 2H); 2.80(t, 2H); 2.90-3.08 (m, 2H); 3.26-3.47 (m, 3H); 3.55 (m, 2H); 3.94(m,1H); 4.15 (m, 1H); 6.87 (d, 1H); 7.02 (s, 1H); 7.13-7.33 (m, 3H); 7.49(s, 1H); 8.40(d, 2H); 11.12 (br.s, 1H).

[0320] MS(ES⁺) m/z (M+H)⁺ 616.20

Example 16

[0321]

[0322] Example 16 was prepared from Intermediate MM using a methodanalogous to the preparation of Example 14.

[0323] NMR (400 Mz, 373° K, DMSO-d6): δ1.54 (m, 10H), 1.97 (m, 1H), 2.30(m, 1H), 2.52 (s, 6H), 3.08 (broard s, 4H), 3.19 (t, 2H), 3.42 (m, 2H),3.55 (m, 3H), 3.63 (m, 1H), 3.70 (m, 1H), 6.71 (t, 1H), 6.97 (d of d,1H), 7.26 (d of d, 2H), 7.32 (s, 2H), 7.35 (d, 1H), 7.54 (d, 1H), 8.51(d of d, 2H), 10.98 (s, 1H).

[0324] Mass: ES+ (M+E)=603

[0325] Preparation of Intermediate MM

[0326] Intermediate JJ was prepared using a method analogous to thepreparation of Intermediate NN (see Example 17).

[0327] NMR (300 Mz, DMSO-d6): δ1.28 (broad s, 2H), 1.36 (s, 9H), 1.47(s, 6H), 1.58 (m, 2H), 2.63 (t, 2H), 2.72 (t, 2H), 3.07 (q, 2H), 3.35(m, 2H), 6.88 (m, 2H), 7.21 (d, 1H), 7.34 (s, 1H), 11.60 (s, 1H).

[0328] Mass: ES− (M−H)=476/478

[0329] A mixture of Intermediate JJ (1.43 g, 3.0 mM),2,6-dimethyl-4-trimethylstannane (890 mg, 3.3 mM), and Pd₂(dba)₃ (173mg, 0.15 mM) in toluene (30 ml) under nitrogen was heated under refluxfor 3 hr. Additional stannane and catalyst (as above) were added andreflux was continued for a further 9 hr. The solvent was evaporated andIntermediate KK was isolated by MPLC (70-100% ethyl acetate/isohexanegradient) and triturated with ether.

[0330] Yield=760 mg, 50%.

[0331] NMR (300 Mz, CDCl₃): δ1.37 (s, 9H), 1.52 (m, 2H), 1.65 (m, 8H),2.60 (s, 6H), 2.77 (t, 2H), 3.12 (t, 2H), 3.48 (m, 2H), 3.55 (t, 2H),4.67 (t, 1H), 7.11 (d, 1H), 7.24 (s, 2H), 7.33 (d, 1H), 7.48 (s, 1H),8.36 (s, 1H).

[0332] Mass: ES+ (M+H)=505.

[0333] Intermediate KK. (750 mg, 1.49 mM) was dissolved in TFA (5 ml)and the solution was heated briefly to 50° C. The TFA was evaporated andthe residue was dissolved in ethyl acetate. Excess sat. HCl/ethylacetate was added giving a white precipitate of Intermediate LL as a2HCl salt. This was filtered off, washed with ethyl acetate and etherand dried under hi-vac.

[0334] Yield=616 mg, (87%)

[0335] NMR (300 Mz, DMSO-d6): δ1.44 (m, 2H), 1.50 (s, 6H), 1.59 (m, 2H),2.69 (m, 2H), 2.79 (s, 6H), 3.00 (m, 2H), 3.44 (m, 4H+water), 7.07 (d,1H), 7.45 (d, 1H), 7.60 (s, 2H), 7.92 (s, 2H), 8.3 (broad s, 3H)

[0336] Mass: ES− (M−H)=403

[0337] Intermediate LL ease prepared using a method analogous to thepreparation of Intermediate LL (see Example 1).

[0338] Mass: ES+ (M+H)=549

Example 17

[0339]

[0340] PhenylN′-cyano-N-{2-[5-[2-(diethylamino)-1,1-dimethyl-2-oxoethyl]-2-(4-methylthien-2-yl)-1H-indol-3-yl]ethyl}imidocarbamate(5), 124 mg(0.23 mmol) and 4-pyrrolidin-3-yl pyridine, 170 mg(1.15 mmol)in 2-propanol (2 ml) were refluxed for 24 hr then a further 150 mg amineadded and reflux continued for a further 24 hr. The resulting solutionwas then purified by chromatography on silica (Bond Elut, 20 g), usingincreasing concentrations (1-6%) of methanol in dichloromethane eluent,to give the Example 17, 52 mg(38%) as a pale orange solid.

[0341]¹H-NMR (300 MHz, CDCl₃): δ=0.75 (m, 3H), 1.16 (m, 3H), 1.58 (s,6H), 1.95 (m, 1H), 2.22-2.40 (m, 1H), 2.30 (s, 3H), 2.92 (m, 2H),3.20-3.62 (m, 8H), 3.65-3.84 (m, 3H), 4.60 (t, 1H), 6.88 (s, 1H),7.02-7.14 (m, 3H), 7.16 (s, 1H), 7.31 (d, 1H), 7.40 (s, 1H), 8.45 (s,1H), 8.54 (d, 2H).

[0342] MS: ESP⁺ (M+H)⁺=596.

[0343] Preparation of Intermediate RR

[0344] A mixture of tert-butyl2-{2-bromo-5-[2-(diethylamino)-1,1-dimethyl-2-oxoethyl]-1H-indol-3-yl}ethylcarbamate(Intermediate NN), 240 mg(0.5 mmol), 4-methylthiophene-2-boronic acid(Intermediate OO), 100 mg (0.7 mmol) andtetrakis(triphenylphosphine)palladium(0), 28 mg(5 mol %) in a mixture of1,2-dimethoxyethane (5 ml) and a saturated aqueous solution of sodiumhydrogen carbonate (1.6 ml) were refluxed for 5 hr. then quenched inwater and extracted with tert-butyl methylether. The extract was washedwith water and saturated brine, dried over magnesium sulfate andevaporated to an orange gum. Purified by flash chromatography (Merck9385 silica, 40% ethyl acetate in iso-hexane eluent) to giveIntermediate PP, 234 mg(91%), as a pale orange gum. MS: ESP⁺ (M+H)⁺=498.

[0345] tert-butyl2-[5-[2-(diethylamino)-1,1-dimethyl]-2-oxoethyl]-2-(4-methylthien-2yl)-1H-indol-3-yl]ethylcarbamate(Intermediate PP), 246 mg(0.49 mmol), in ethanol (3 ml) was treated, atroom temperature, with a saturated solution of hydrogen chloride inethanol (3 ml) then the reaction stirred 48 hr. The solvent was thenevaporated in vacuo to give Intermediate QQ as a pale green solid whichwas triturated with diethyl ether, filtered and dried. Yield 130mg(61%).

[0346]¹H-NMR (300 MHz, DMSO-d6): δ=0.65 (m, 3H), 1.07 (m, 3H), 1.48 (s,6H), 2.30 (s, 3H), 2.80-3.00 (m, 4H), 3.15-3.30 (m, 4H), 6.93 (dd, 1H),7.23 (d, 1H), 7.32 (d, 1H), 7.35 (s, 1H), 7.43 (d, 1H), 8.14(broad s,3H).

[0347] MS: ESP⁺ (M+H)⁺=398.

[0348]2-[3-(2-aminoethyl)-2-(4-methylthien-2-yl)-1H-indol-5-yl]-N,N-diethyl-2-methylpropanamideIntermediate QQ (hydrochloride salt), 100 mg(0.23 mmol), diphenylcyanocarbonimidate, 58 mg(0.24 mmol) and triethylamine, 23 mg(0.23 mmol)in 2-propanol (5 ml) were stirred at room temperature for 8 hr then leftto stand overnight. The resulting solution was purified by flashchromatography (Merck 9385 silica, 70% ethyl acetate in iso-hexaneeluent) to give Intermediate RR, 124 mg(99%), as a colourless gum.

[0349] MS: ESP⁺ (M+H)⁺=542.

[0350] Preparation of Intermediate NN

[0351] A solution of Intermediate F (see Example 1) (7.2 g, 20 mmol) and4-Chlorobutyraldehyde dimethyl acetal (2.64 g, 20 mmol) in EtOH (200 mL)and water (40 mL) was heated at 95° C. for 18 hrs. The RM wasconcentrated and the residues treated with satd NaHCO3 (aq) to giveIntermediate SS as a yellow solid which was collected by filtration anddried. 2.0 g (26.5%)

[0352]¹H NMR (300 MHz, CDCl₃) δ0.6-0.8 (m,3H); 1.04-1.2 (m,3H); 1.5-1.7(bs,8H); 2.8-2.94 (m,4H); 2.95-3.03 (m,2H); 3.26-3.42 (m,2H); 7.1(s,1H); 7.22 (s,1H); 7.35 (s, 1H); 8.48 (bs,1H).

[0353] MS (ES⁺) m/z (M)⁺ 380.13

[0354] Intermediate SS (6.0 g,15.8 mmol) was reduced analogously as forthe preparation of Intermediate J (see Example 1) to give IntermediateTT as a brown foam, 3.8 g (80%).

[0355]¹H NMR (300 MHz, CDCl₃) δ0.63 (m,3H); 1.10 (m,3H); 1.52 (s,6H);1.6 (bs,2H); 2.83 (m,4H); 2.95 (t,2H); 3.3 (m,2H); 6.97 (d,1H); 6.98(dd,1H); 7.23 (d,1H); 7.35 (s,1H); 8.1 (bs,₁H).

[0356] MS (ES⁺) m/z (M+H)⁺ 302

[0357] To a stirred solution of Intermediate TT (3.01 g, 10 mM) inacetic acid (40 ml), was added 5.5M HBr/acetic acid (1.82 ml, 10 mM),followed by 2.0M bromine/acetic acid (5.5 ml, 11.0 mM). The solvent wasevaporated under reduced pressure and the residue (Intermediate UU) wastaken into ethyl acetate. It was washed with aq. ammonia and brine,dried over anh. sodium sulphate and evaporated to a gum. This was notcharacterised and was used without purification.

[0358] To a solution of Intermediate UU (3.33 mM) in dichloromethane (10ml) was added Boc-O-Boc (5.0 mM, 1.09 g) and the solution was stirredfor 30 mins. The solution was evaporated to ˜5 ml and applied directlyto a MPLC column, eluting with 40% ethyl acetate/isohexane. IntermediateNN was isolated as a crisp foam on evaporation.

[0359] Yield=895 mg, 56% (2 stages).

[0360] NMR (300 Mz, DMSO-d6) δ0.56 (broad s, 3H), 1.00 (broad s, 3H),1.35 (s, 9H), 1.45 (s, 6H), 2.70 (t, 2H), 2.80 (broad s, 2H), 3.07 (q,2H), 3.20 (broad s, 2H), 6.82 (m, 1H), 6.86 (d of d, 1H), 7.20 (d, 1H),7.30 (s, 1H), 11.53 (s, 1H).

[0361] Mass: ES− (M−H)=480

[0362] Therapeutic Uses

[0363] Compounds of formula I are provided as medicaments forantagonising gonadotropin releasing hormone (GnRH) activity in apatient, eg, in men and/or women. To this end, a compound of formula Ican be provided as part of a pharmaceutical formulation which alsoincludes a pharmaceutically acceptable diluent or carrier (eg, water).The formulation may be in the form of tablets, capsules, granules,powders, syrups, emulsions (eg, lipid emulsions), suppositories,ointments, creams, drops, suspensions (eg, aqueous or oily suspensions)or solutions (eg, aqueous or oily solutions). If desired, theformulation may include one or more additional substances independentlyselected from stabilising agents, wetting agents, emulsifying agents,buffers, lactose, sialic acid, magnesium stearate, terra alba, sucrose,corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacaobutter and ethylene glycol.

[0364] The compound is preferably orally administered to a patient, butother routes of administration are possible, such as parenteral orrectal administration. For intravenous, subcutaneous or intramuscularadministration, the patient may receive a daily dose of 0.1 mgkg⁻¹ to 30mgkg⁻¹ (preferably, 5 mgkg⁻¹ to 20 mgkg⁻¹) of the compound, the compoundbeing administered 1 to 4 times per day. The intravenous, subcutaneousand intramuscular dose may be given by means of a bolus injection.Alternatively, the intravenous dose may be given by continuous infusionover a period of time. Alternatively, the patient may receive a dailyoral dose which is approximately equivalent to the daily parenteraldose, the composition being administered 1 to 4 times per day. Asuitable pharmaceutical formulation is one suitable for oraladministration in unit dosage form, for example as a tablet or capsule,which contains between 10 mg and 1 g (preferably, 100 mg and 1 g) of thecompound of the invention.

[0365] The following illustrate representative pharmaceutical dosageforms containing a compound of the invention, or a pharmaceuticallyacceptable salt or solvate thereof (hereafter referred to as “compoundX”), for use in humans. (a) Tablet I mg/tablet Compound X. 100 LactosePh.Eur. 179 Croscarmellose sodium 12.0 Polyvinylpyrrolidone 6 Magnesiumstearate 3.0 (b) Tablet II mg/tablet Compound X 50 Lactose Ph.Eur. 229Croscarmellose sodium 12.0 Polyvinylpyrrolidone 6 Magnesium stearate 3.0(c) Tablet III mg/tablet Compound X 1.0 Lactose Ph.Eur. 92Croscarmellose sodium 4.0 Polyvinylpyrrolidone 2.0 Magnesium stearate1.0 (d) Capsule mg/capsule Compound X 10 Lactose Ph.Eur. 389Croscarmellose sodium 100 Magnesium stearate 1. (e) Injection I (50mg/ml) Compound X 5.0% w/v Isotonic aqueous solution to 100%

[0366] Buffers, pharmaceutically acceptable cosolvents (eg, polyethyleneglycol, propylene glycol, glycerol or EtOH) or complexing agents such ashydroxy-propyl β cyclodextrin may be used to aid formulation.

[0367] One aspect of the invention relates to the use of compoundsaccording to the invention for reducing the secretion of LH and/or FSHby the pituitary gland of a patient. In this respect, the reduction maybe by way of a reduction in biosynthesis of the LH and FSH and/or areduction in the release of LH and FSH by the pituitary gland. Thus,compounds according to the invention can be used for therapeuticallytreating and/or preventing a sex hormone related condition in thepatient. By “preventing” we mean reducing the patient's risk ofcontracting the condition. By “treating” we mean eradicating thecondition or reducing its severity in the patient. Examples of sexhormone related conditions are: a sex hormone dependent cancer, benignprostatic hypertrophy, myoma of the uterus, endometriosis, polycysticovarian disease, uterine fibroids, prostatauxe, myorna uteri, hirsutismand precocious puberty. Examples of sex hormone dependent cancers are:prostatic cancer, uterine cancer, breast cancer and pituitarygonadotrophe adenoma.

[0368] Assays

[0369] The ability of compounds according to the invention to act asantagonists of GnRH can be determined using the following in vitroassays.

[0370] Binding Assay Using Rat Pituitary GnRH Receptor

[0371] The assay is performed as follows:

[0372] 1. Incubate crude plasma membranes prepared from rat pituitarytissues in a Tris.HCl buffer (pH. 7.5, 50 mM) containing bovine serumalbumin (0.1%), [I-125]D-t-Bu-Ser6-Pro9-ethyl anide-GnRH, and the testcompound. Incubation is at 4° C. for 90 minutes to 2 hours.

[0373] 2. Rapidly filter and repeatedly wash through a glass fibrefilter.

[0374] 3. Determine the radioactivity of membrane bound radio-ligandsusing a gamma counter.

[0375] From this data, the IC₅₀ of the test compound can be determinedas the concentration of the compound required to inhibit radio-ligandbinding to GnRH receptors by 50%. Compounds according to the presentinvention have activity at a concentration from 1 nM to 5 μM.

[0376] Binding Assay Using Human GnRH Receptor

[0377] Crude membranes prepared from CHO cells expressing human GnRHreceptors are sources for the GnRH receptor. The binding activity ofcompounds according to the invention can be determined as an IC₅₀ whichis the compound concentration required to inhibit the specific bindingof [¹²⁵I]buserelin to GnRH receptors by 50%. [¹²⁵I]Buserelin (a peptideGnRH analogue) is used here as a radiolabelled ligand of the receptor.

[0378] Assay to Determine Inhibition of LH Release

[0379] The LH release assay can be used to demonstrate antagonistactivity of compounds, as demonstrated by a reduction in GnRH-induced LHrelease.

[0380] Preparation of Pituitary Glands

[0381] Pituitary glands obtained from rats are prepared as follows.Suitable rats are Wistar male rats (150-200 g) which have beenmaintained at a constant temperature (eg, 25° C.) on a 12 hour light/12hour dark cycle. The rats are sacrificed by decapitation before thepituitary glands are aseptically removed to tube containing Hank'sBalanced Salt Solution (HBSS).

[0382] The glands are further processed by:

[0383] 1. Centrifugation at 250×g for 5 minutes;

[0384] 2. Aspiration of the HBSS solution;

[0385] 3. Transfer of the glands to a petri dish before mincing with ascalpel;

[0386] 4. Transfer of the minced tissue to a centrifuge tube bysuspending the tissue three successive times in 10 ml aliquots of HBSScontaining 0.2% collagenase and 0.2% hyaluronidase;

[0387] 5. Cell dispersion by gentle stirring of the tissue suspensionwhile the tube is kept in a water bath at 37° C.;

[0388] 6. Aspiration 20 to 30 times using a pipette, undigestedpituitary fragments being allowed to settle for 3 to 5 minutes;

[0389] 7. Aspiration of the suspended cells followed by centrifugationat 1200×g for 5 minutes;

[0390] 8. Resuspension of the cells in culture medium of DMEM containing0.37% NaHCO₃, 10% horse serum, 2.5% foetal bovine serum, 1% nonessential amino acids, 1% glutamine and 0.1% gentamycin;

[0391] 9. Treatment of the undigested pituitary fragments 3 times with30 ml aliquots of the collagenase and hyaluronidase.

[0392] 10. Pooling of the cell suspensions and dilution to aconcentration of 3×10⁵ cells/ml;

[0393] 11. Placing of 1.0 ml of this suspension in each of a 24 welltray, with the cells being maintained in a humidified 5% CO₂/95% airatmosphere at 37° C. for 3 to 4 days

[0394] Testing of Compounds

[0395] The test compound is dissolved in DMSO to a final concentrationof 0.5% in the incubation medium.

[0396] 1.5 hours prior to the assay, tie cells are washed three timeswith DMEM containing 0.37% NaHCO₃, 10% horse serum, 2.5% foetal bovineserum, 1% non essential amino acids (100×), 1% glutamine (100×), 1%penicillin/streptomycin (10,000 units of each per ml) and 25 mM HEPES atpH 7.4. Immediately prior to the assay, the cells are again washed twicein this medium.

[0397] Following this, 1 ml of fresh medium containing the test compoundand 2 nM GnRH is added to two wells. For other test compounds (where itis desired to test more than one compound), these are added to otherrespective duplicate wells. Incubation is then carried out at 37° C. forthree hours.

[0398] Following incubation, each well is analysed by removing themedium from the well and centrifuging the medium at 2000×g for 15minutes to remove any cellular material. The supernatant is removed andassayed for LH content using a double antibody radio-immuno assay.Comparison with a suitable control (no test compound) is used todetermine whether the test compound reduces LH release. Compoundsaccording to the present invention have activity at a concentration from1 nM to 5 μM,

1. A compound of formula I or a pharmaceutically acceptable salt orsolvate thereof

For A, either: (i) A represents a single bond; optionally substituted C1to C8 alkylene; a C2 to C12 group having at least one alkene doublebond; a 3- to 8-membered heterocyctic ring containing from 1 to 4heteroatoms independently selected from O, N and S or —R—Ar—R′—, where Rand R′ are independently selected from a bond, optionally substituted C1to C8 alkylene and a C2 to C12 group having at least one alkene doublebond; and Ar represents optionally substituted aryl; or (ii) thestructure N—A(—R4) represents a 3- to 8-membered heterocyclic ringoptionally containing from 1 to 3 further heteroatoms independentlyselected from O, N and S, N—A(—R4) being optionally substituted; Brepresents a bond or optionally substituted C1 to C5 alkylene; Crepresents a mono- or bi-cyclic aromatic ring structure optionallyhaving at least one substituent selected from CN; NR5R6; an optionallysubstituted C1 to C8 alkyl; optionally substituted C1 to C8 alkoxy;halogen; D represents hydrogen; optionally substituted C1 to C8 alkyl;or (CH₂)_(b)—R, wherein R represents C3 to C8 cycloalkyl; E is selectedfrom an optionally substituted 3- to 8-membered heterocyclic ringcontaining from 1 to 4 heteroatoms independently selected from O, N andS; II; III; IV; V; VI and VII

 wherein het represents an optionally substituted 3- to 8-memberedheterocyclic ring containing from 1 to 4 heteroatoms independentlyselected from O, N and S; F is optionally substituted and representsphenyl or a 3- to 8-membered heterocyclic ring containing from 1 to 4heteroatoms independently selected from O, N and S; For X and Y, either:(iii) X represents N and Y represents CN or H; or X represents CH and Yrepresents NO₂; or (iv) X—Y represents O; For R1 and R2, either: (v) R1and R2 are independently selected from hydrogen and optionallysubstituted C1 to C8 alkyl; or (vi) R1 and R2 together representcarbonyl; or (vii)

 represents an optionally substituted 3- to 8-membered heterocyclic ringcontaining from 1 to 3 further heteroatoms independently selected fromO, N and S, and R2 meets the definition in option (v); R3 meets thedefinition in option (vii) or represents hydrogen or optionallysubstituted C1 to C8 alkyl; R4 meets the definition in option (ii) orrepresents hydrogen or optionally substituted C1 to C8 alkyl; R5 and R6are independently selected from H; optionally substituted C1 to C8 alkyland optionally substituted aryl; For R7 and R7a, either: (viii) R7 andR7a are independently selected from H or optionally substituted C1 to C8alkyl; or (ix)

 represents an optionally substituted 3 to 7-membered cycloalkyl ring;For R8 and R9, either: (x) R8 is selected from H; optionally substitutedC1 to C8 alkyl; optionally substituted aryl; —R—Ar, where R representsC1 to C8 alkylene and Ar represents optionally substituted aryl; and anoptionally substituted 3- to 8-membered heterocyclic ring optionallycontaining from 1 to 3 further heteroatoms independently selected fromO, N and S; and R9 is selected from H; optionally substituted C1 to C8alkyl and optionally substituted aryl; or (xi) wherein E representsstructure II or III, NR8(—R9) represents an optionally substituted 3- to8-membered heterocyclic ring optionally containing from 1 to 3 furtherheteroatoms independently selected from O, N and S; or (xii)wherein Erepresents structure VI,

 represents an optionally substituted 3- to 8-membered heterocyclic ringoptionally containing from 1 to 4 heteroatoms independently selectedfrom O, N and S; b represents zero or an integer from 1 to
 6. 2. Thecompound of claim 1, wherein F is optionally substituted and representspyridyl, VIII, IX, X, XI, XII, XIII, XIV or XIVa

wherein R10 represents hydrogen; optionally substituted C1 to C8 alkyl;OH; halogen; CN; C1 to C8 alkoxy; or CF₃; and R10′ represents hydrogenor optionally substituted C1 to C8 alkyl.
 3. The compound of claim 1 or2, wherein, E represents one of the following groups


4. The compound of any preceding claim, wherein C represents

wherein Me represents methyl.
 5. The compound of any preceding claim,wherein X represents CH and Y represents NO₂.
 6. The compound of any oneof claims 1 to 4, wherein X represents N and Y represents CN.
 7. Thecompound of any one of claims 1 to 4, wherein X and Y represent O. 8.The compound of any preceding claim, wherein R1 and R2 each represent Hand B represents C1 alkylene.
 9. The compound of claim 1, wherein thecompound is selected from2-(2-(3,5-dimethylphenyl)-3-{2-[(2-nitro-1-{[2-(4-pyridinyl)ethyl]amino}ethenyl)amino]ethyl}-1H-indol-5-yl)-N,N-diethyl-2-methylpropanamide;2-[3-2{-[((cyanoimino){[2-(4-pyridinyl)ethyl]amino}methyl)amino]ethyl}-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-N,N-diethyl-2-methylpropanamide;2-[3-2{-[((cyanoimino){[2-(2-pyridinyl)ethyl]amino}methyl)amino]ethyl}-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-N,N-diethyl-2-methylpropanamide;2-[3-2{-[((cyanoimino){[2-(1-imidazoyl)ethyl]amino}methyl)amino]ethyl}-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-N,N-diethyl-2-methylpropanamide;2-[2-(3,5-dimethylphenyl)-3-(2-{[(phenethylamino)carbonyl]amino}ethyl)-1H-indol-5-yl]-N,N-diethyl-2-methylpropanamide;2-[2-(3,5-dimethylphenyl)-3-(2-{[(4-pyridinyl)ethyl]amino)carbonyl]amino}ethyl)-1H-indol-5-yl]-N,N-diethyl-2-methylpropanamide;2-[3-2{-[((cyanoimino){[3-(4-methylpiperazino)propyl]amino}methyl)amino]ethyl}-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-N,N-diethyl-2-methylpropanamide;2-[3-2{-[((cyanoimino){[2-(2-piperidinyl)ethyl]amino}methyl)amino]ethyl}-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-N,N-diethyl-2-methylpropanamide;2-[3-[2-({(cyanoimino)[3-(4-pyridinyl)-pyrrolidin-1-yl]methyl}Iamino)ethyl]-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-N,N-diethyl-2-methylpropanamide;2-[3-2{-[((cyanoimino){[2-(4-pyridinyl)ethyl]aminomethyl}methyl)amino]ethyl}-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-N,N-diethyl-2-methylpropanamide;2-[3-[2-[(2-nitro-1-([3-(4-pyridinyl)-pyrrolidin-1-yl]ethenyl}amino)ethyl]-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-N,N-diethyl-2-methylpropanamide;2-[3-[2-((carbonyl)[3-(4-pyridinyl)-pyrrolidin-1-yl]amino)ethyl]-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-N,N-diethyl-2-methylpropanamide;2-[3-(2-[{(imino)[3-(4-pyridinyl)-pyrrolidin-1-yl]methyl}amino)ethyl]-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-N,N-diethyl-2-methylpropanamide;and2-[3-[2-({(cyanoimino)[3-(4-pyridinyl)-pyrrolidin-1-yl]methyl}amino)ethyl]-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-1-cyclopropylcarboxylicacid-diethylamide.
 10. A compound according to any preceding claim foruse as a medicament.
 11. A pharmaceutical formulation comprising acompound according to any one of claims 1 to 9 and a pharmaceuticallyacceptable diluent or carrier.
 12. Use of a compound according to anyone of claims 1 to 9, in the manufacture of a medicament, forantagonising gonadotropin releasing hormone activity.
 13. Use of acompound according to any one of claims 1 to 9, in the manufacture of amedicament for administration to a patient, for reducing the secretionof luteinising hormone by the pituitary gland of the patient.
 14. Use ofa compound according to any one of claims 1 to 9, in the manufacture ofa medicament for administration to a patient, for therapeuticallytreating and/or preventing a sex hormone related condition in thepatient.
 15. The use according to claim 14, wherein the sex hormonerelated condition is selected from a sex hormone dependent cancer,benign prostatic hypertrophy or myoma of the uterus.
 16. The useaccording to claim 15, wherein the sex hormone dependent cancer isselected from prostatic cancer, uterine cancer, breast cancer andpituitary gonadotrophe adenoma.
 17. A method of antagonisinggonadotropin releasing hormone activity in a patient, comprisingadministering to the patient a compound according to any one of claims 1to
 9. 18. A process of producing a compound according to any one ofclaims 1 to 9, wherein the process comprises a reaction step selectedfrom steps (a) to (e): (a) Reaction of XV as follows

(b) Cleavage of the CN group of XVI in the presence of acid to produceXVII

(c) Reaction of XVIII as follows

(d) Reaction of XX as follows

(e) Reaction of XXII as follows